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Cancer pain management: Role of adjuvant analgesics (coanalgesics)

Cancer pain management: Role of adjuvant analgesics (coanalgesics)
Literature review current through: Jan 2024.
This topic last updated: Dec 16, 2022.

INTRODUCTION — Opioid therapy is the first-line approach for moderate or severe chronic pain in populations with active cancer. If opioid therapy by itself yields a good outcome (satisfactory analgesia, tolerable side effects, and treatment adherence) additional analgesic interventions are not needed. Should the patient demonstrate a poor response to the opioid, however, therapy must be changed. This common scenario may be addressed in many ways, among which is the addition of another analgesic drug.

In some cases, the use of a nonopioid analgesic, such as acetaminophen (paracetamol) or a nonsteroidal anti-inflammatory drug (NSAID), is appropriate and sufficient. In others, significant benefit may be obtained by the addition of a so-called "adjuvant analgesic" or coanalgesic. This topic review will cover the use of adjuvant analgesics in cancer pain management. Assessment of cancer pain, a review of specific cancer pain syndromes, clinical use and side effects of opioid analgesics, use of acetaminophen and NSAIDs in patients with cancer pain, and nonpharmacologic methods of cancer pain management are covered elsewhere. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'General principles of pain management' and "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs".)

DEFINITION OF AN ADJUVANT ANALGESIC — The term "adjuvant analgesic" originally referred to a small number of drugs that were approved and marketed for indications other than pain but were found to be potentially useful as analgesics in patients receiving opioid therapy. Over the past three decades, the number and types of these nontraditional analgesics has increased dramatically [1]. Some are now commonly used as single entity treatments for chronic pain and several have been approved for pain indications in the United States and elsewhere. As such, the term "adjuvant analgesic" as used originally, is a misnomer. However, a simple definition that applies in all settings states that an "adjuvant analgesic" is a drug that has a clinical use other than pain but is used as an analgesic in selected circumstances.

In the context of cancer pain, however, the designation of adjuvant analgesic is still apt given the typical co-administration of an adjuvant drug with an opioid, and the term "coanalgesic" is synonymous.

Integration into cancer pain management

Timing of an adjuvant analgesic — There are no published data that inform the decision about the timing of adjuvant analgesic therapy in patients with cancer-related pain and this is a matter of clinical judgment. We base our decision, in part, on whether the patient has active cancer or is a cancer survivor. In contrast to patients with active cancer, in whom adjuvant analgesics may be added to opioids if chronic pain is poorly responsive to opioids, cancer survivors with chronic (typically neuropathic) pain usually receive an initial trial of an adjuvant analgesics, and opioids are only considered on a case-by-case basis, after other therapeutic trials have been ineffective. This more limited role reflects concern about the ongoing risks associated with opioid drugs and the need for careful long-term management of adverse effects related to both drug toxicities and abuse. (See 'General principles' below.)

Adjuvant analgesics are often considered for treatment of chronic mild, moderate, or severe cancer pain when a patient is poorly responsive to opioids (ie, inability to titrate the opioid to a dose that maintains a favorable balance between analgesia and side effects). The addition of an adjuvant analgesic is one approach among many that may be considered for such patients [2]. Alternative approaches may include rotation to a different opioid, more aggressive treatment of the side effect that is limiting dose escalation, or a trial of an intervention (such as a nerve block) or other nonpharmacologic treatment. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Dose titration' and "Prevention and management of side effects in patients receiving opioids for chronic pain".)

Although the role of the adjuvant analgesics in addressing pain that has not been opioid responsive suggests that these drugs are typically tried after the opioid regimen has been optimized, there is variability in the timing of adjuvant analgesic therapy in clinical practice. In a setting where a patient may benefit from a nonanalgesic effect of the adjuvant drug (eg, mood enhancement from an analgesic antidepressant or a reduction in skeletal-related events from a bisphosphonate), early administration of the adjuvant analgesic, before the full effect of an opioid has been ascertained, is reasonable and may in fact be preferable. On the other hand, if the primary outcome of interest is analgesia (eg, the use of a gabapentin for the treatment of cancer-related neuropathic pain), some experts believe that treatment should be delayed until efforts have been made to optimize opioid therapy, while others believe that early use, in tandem with cautious opioid titration, produces better outcomes associated with an opioid-sparing effect. The potential benefits associated with delaying the trial of an adjuvant analgesic in this setting includes ensuring that the drug is needed, reducing the risk of additive toxicity by sequencing drug titration efforts, and limiting confusion as to the source of an adverse drug effect should one arise. This approach of delaying initiation of the adjuvant analgesic gains limited support from a systematic review [3].

Available agents and dose ranges — Based upon conventional practice, the categories of available agents used commonly for cancer pain include (table 1):

Drugs potentially useful for any type of pain (multipurpose analgesics)

Drugs used for treatment of neuropathic pain

Drugs used for bone pain

Drugs used for pain and other symptoms in the setting of bowel obstruction

With just a few exceptions, recommendations for multipurpose analgesics and the drugs used for neuropathic pain in the cancer population are based upon clinical experience and data derived from studies of populations with chronic noncancer pain, particularly populations with neuropathic pain [1]. This information is evolving as new trials are conducted, and as clinical experience expands with newer agents.

Commonly used adjuvant analgesics are described in the table (table 2). For most drugs, effective dose ranges vary and many require dose titration, a gradual incrementing of the dose from a relatively low starting dose until the analgesic effect is achieved, adverse effects become unmanageable, or the conventional maximal dose is achieved.

ANY TYPE OF CHRONIC PAIN: MULTIPURPOSE ANALGESICS — Some drug classes, including the glucocorticoids, antidepressants, alpha-2 adrenergic agonists, cannabinoids, some topical therapies, and botulinum toxin have been studied in diverse types of chronic pain, and the available data suggest the potential for efficacy in multiple types of chronic pain, including cancer pain. These drugs may therefore be considered multipurpose analgesics.

Glucocorticoids

Indications — Recommendations for use of glucocorticoids in the treatment of cancer-related pain are not evidence-based due to limitations in the existing literature. Randomized trials that have been conducted to assess the analgesic properties of glucocorticoids in cancer patients have been small and have produced mixed results [4-11]. A 2015 systematic review of six randomized trials found that glucocorticoid therapy resulted in modestly less pain compared with control treatment (placebo or usual treatment/supportive care) at one week (mean difference on a 1 to 10 numeric pain scale of 0.84 [95% CI 1.38-0.30]) [12]. The quality of the evidence was weak and the authors concluded that additional trials are needed to evaluate the safety and effectiveness of glucocorticoids for management of cancer pain in adults. (See "Assessment of cancer pain", section on 'Nociceptive pain' and "Management of vasogenic edema in patients with primary and metastatic brain tumors" and "Treatment and prognosis of neoplastic epidural spinal cord compression".)

Notwithstanding this limited evidence, there is a large clinical experience suggesting that glucocorticoids can be useful in the treatment of a variety of types of cancer pain, including neuropathic and bone pain, pain associated with stretch of an organ capsule caused by a space-occupying lesion (eg, within the liver or kidney) or duct obstruction, pain from malignant bowel obstruction, pain caused by lymphedema, and headache caused by increased intracranial pressure. Using these drugs for cancer pain, however, always must consider the potential for toxicity associated with long-term administration, particularly at higher doses. Treatment for just several weeks may cause myopathy, immunocompromise, glucose intolerance, psychotomimetic effects, and hypoadrenalism. (See "Major adverse effects of systemic glucocorticoids".)

Because of this potential for toxicity, a careful risk-to-benefit analysis is warranted whenever a glucocorticoid is being considered for pain management. This analysis should weigh the availability of other treatments and the planned duration of treatment, the presence of other symptoms, the treatment context, and the patient's life expectancy. As examples:

In the context of advanced illness and a very short prognosis (ie, days to weeks), some experts favor a trial of a glucocorticoid drug at a relatively low dose to address pain and other common symptoms, such as nausea, fatigue, or dysphoria. This treatment usually is continued until the death of the patient.

In other contexts, such as severe neuropathic pain in a patient with longer life expectancy, the risks of prolonged glucocorticoid treatment are usually considered too substantial to consider open-ended therapy. Instead, short-term treatment (ie, a "glucocorticoid pulse") is a reasonable option. As an example, two weeks of a gradually tapering regimen may be useful for patients with severe neuropathic pain to promote pain control while a different neuropathic agent (eg, pregabalin) is titrated to levels that provide pain relief. (See 'Choice of agent and dose' below.)

The use of glucocorticoids for specific types of cancer-related pain, including pain from bone metastases, and the pain associated with malignant bowel obstruction, are discussed below. (See 'Patients with bone pain' below and 'Patients with malignant bowel obstruction' below.)

Choice of agent and dose — Dexamethasone is usually preferred for the management of cancer-related pain, presumably because of its long half-life and relatively low mineralocorticoid effects (table 3). However, there is no empiric evidence that this drug is either safer or more effective in the cancer population than any other glucocorticoid. Prednisone and methylprednisolone are acceptable alternatives. (See "Pharmacologic use of glucocorticoids".)

The dose and frequency should be selected based on the cause of pain, and its severity. For those experts who favor a trial of low-dose glucocorticoid for pain and other symptoms in the context of advanced cancer and short prognosis, a typical regimen, based on clinical experience, is prednisone 5mg once or twice daily or dexamethasone 0.75 to 1.5 mg once or twice daily.

There are some situations for which a brief regimen of higher-dose glucocorticoids might be appropriate. When short-term therapy (a "glucocorticoid pulse") is considered (eg, when a patient has a "pain crisis" with escalating pain and distress that do not respond well to an initial opioid therapy), a loading bolus may be used. In the past, the size of the loading bolus and the initial doses that follow were adapted from an approach used to manage acute and emerging epidural spinal cord compression (ESCC; including cauda equina syndrome). This approach, which included a dexamethasone loading dose as high as 96 mg followed by a rapid taper beginning at 24 mg four times daily, was believed to yield prompt pain relief and potentially better outcomes after treatment of the tumor. More recently, however, this approach to ESCC has been questioned because good evidence of benefit (particularly a favorable risk-to-benefit ratio) is lacking [13]. More recent guidelines endorse a lower dose glucocorticoid regimen (dexamethasone 10 mg loading dose followed by 4 to 6 mg four times daily) in this setting [14]. (See "Treatment and prognosis of neoplastic epidural spinal cord compression", section on 'Glucocorticoids'.)

Given this changing perspective, some experts would still consider a higher-dose glucocorticoid regimen when managing patients with "pain crisis" who have not experienced rapid relief following opioid administration, but the interpretation of "high-dose" has become more conservative. When pain is severe and escalating despite opioid treatment, and patient distress is very high, treatment with a regimen of a test dose of 8 to 10 mg dexamethasone, to determine if the pain is steroid responsive, can be used. If there is a dramatic response, then 4 mg bid or 8 mg daily can be tried, and the dose down-titrated to the lowest dose that maintains pain relief while other analgesic treatments are added, if indicated.

Analgesic antidepressants

Indications — For a patient with chronic cancer pain that is poorly responsive to opioid therapy who also has a depressed mood, we suggest an early trial of an analgesic antidepressant rather than a different adjuvant analgesic.

Antidepressants have been widely studied in populations with chronic pain from a variety of conditions, and several meta-analyses have concluded that these drugs act as multipurpose analgesics and are effective for a wide range of pain conditions, including low back pain, various types of neuropathic pain, and fibromyalgia [1,15-22]. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Antidepressants'.)

Although very few of these studies have included cancer patients, the utility of these drugs for cancer pain is assumed and they are usually considered for patients with neuropathic pain that has not promptly responded to an opioid. However, given the range of their potential analgesic efficacy, they also could be considered for any type of chronic cancer pain that has not responded adequately to opioid therapy. (See 'Patients with neuropathic pain' below and "Assessment of cancer pain", section on 'Neuropathic pain'.)

Mechanism of analgesic effect — Antidepressants function as primary analgesics. Although pain reduction may be enhanced if there is a positive mood effect, analgesia is not dependent on mood elevation, and pain can be improved in euthymic patients. An early trial when pain is accompanied by depressed mood is appropriate in the hope of achieving a separate and positive effect on mood.

The antidepressant's primary analgesic mode of action is thought to be related to the enhanced availability of monoamines at synapses within neural pathways that are part of a descending pain modulating system. Inhibition of norepinephrine reuptake appears to be the most important mode of action, but serotonergic and dopaminergic effects also may play a role in analgesia [23].

Selection of agent and dose — Given the more favorable side effect profile over tricyclic antidepressants (TCAs), among patients with serious medical illness, such as those with cancer, we consider a serotonin-norepinephrine reuptake inhibitor (SNRI; usually duloxetine) to be the first-line analgesic antidepressant, followed by a secondary TCA (usually desipramine). Given its activating effect, a trial of bupropion is reasonable if cancer pain is complicated by fatigue or somnolence, even though the evidence of analgesic efficacy is weak. Bupropion should be avoided in patients at risk for seizures.

Antidepressants comprise several subclasses and numerous drugs (table 1). Analgesic efficacy is best established for some of the TCA compounds [24-26] and the SNRIs [26-30] (although benefit from venlafaxine is debated [31]). There is minimal evidence of analgesic efficacy with the serotonin-selective reuptake inhibitors (SSRIs) [32,33]. Benefit has also been suggested for bupropion (a dopamine reuptake inhibitor) in patients with neuropathic pain, although the evidence is not robust [34,35].

The side effect profile of SNRIs (which includes nausea, sexual dysfunction, and somnolence or mental clouding) is more favorable relative to desipramine and nortriptyline, although there is a great deal of interindividual variation [36]. The SNRIs include duloxetine, milnacipran, venlafaxine, and desvenlafaxine. Evidence of analgesic effects is best established for duloxetine [28-30,37]. A five-week randomized trial of duloxetine in patients with chemotherapy-induced painful peripheral neuropathy associated with taxanes or platinum agents found that the drug was analgesic at a dose of 30 to 60 mg [37]. There are no analgesic trials comparing different drugs within the SNRI class. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Duloxetine'.)

The TCAs include tertiary amine compounds, such as amitriptyline, and secondary amine compounds, such as nortriptyline and desipramine. The secondary amine drugs, which are more selective at noradrenergic reuptake sites, have a more favorable side effect profile than amitriptyline [36]. As a result, when a TCA is chosen in a medically ill patient, desipramine or nortriptyline is usually preferred. All of the TCAs are relatively contraindicated in patients with serious heart disease, severe prostatic hypertrophy, and narrow-angle glaucoma. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Side effects'.)

Given the potential for a dose-response relationship for pain [24] and a desire to avoid initial toxicity, all of the analgesic antidepressants should be started at a relatively low initial dose (table 2). The dose may be increased in steps until benefit occurs, side effects supervene, or the conventional maximal dose has been reached. For the SNRIs, dose titration typically involves one or two increments; for the TCAs, many steps may be taken to explore the potential therapeutic range (dose or serum level, if this is measured). The starting dose for a trial of desipramine, for example, is 10 to 25 mg at night. The dose should be increased no more quickly than every few days in the absence of satisfactory relief or side effects, and the maximum dose may be 150 to 300 mg at night. Analgesia typically appears within a week of starting a dose (developing more rapidly than the antidepressant effects) and most patients who experience pain relief respond at a dose between 50 and 150 mg per day.

When relatively high doses of the TCA antidepressants are used (ie, above 100 mg per day), the plasma drug concentration and an electrocardiogram should be monitored. TCAs can prolong the QTc interval and predispose to cardiac arrhythmias, and should be used cautiously when a patient has known heart disease or is receiving other drugs (including methadone) that can prolong the QTc interval.

Unlike the tricyclics, duloxetine and bupropion do not prolong the QTc interval. However, gastrointestinal side effects (including nausea, dry mouth, and constipation) are common with duloxetine, and bupropion causes jitteriness or headache as relatively common initial side effects.

Discontinuation — It is always preferable to taper the antidepressants before discontinuing them if treatment has been given for more than several weeks, particularly at higher doses. Discontinuation symptoms may occur with all antidepressants and have been best described for both SNRIs and SSRIs. The antidepressant discontinuation syndrome caused by these drugs may include flu-like symptoms and signs, and psychiatric phenomena [38]. (See "Discontinuing antidepressant medications in adults", section on 'Discontinuation syndrome'.)

Alpha-2 adrenergic agonists — A trial of tizanidine, an alpha-2 adrenergic agonist, is an option for patients who have opioid-refractory chronic pain if other adjuvant analgesics have not helped. Patients who are hemodynamically unstable or predisposed to hypotension (eg, by autonomic neuropathy, intravascular volume depletion, or concurrent therapy with potent hypotensive agents) are not appropriate candidates. Like other centrally-acting drugs with prominent sedative effects, it must be used cautiously in patients with acute or chronic encephalopathy of any cause.

The analgesic effects produced by the alpha-2 adrenergic agonists, including clonidine, tizanidine, and dexmedetomidine, have been demonstrated in both animal and human studies. Clonidine may be analgesic when administered orally, transdermally, or intraspinally [39-41]; most studies in cancer-related pain have involved neuraxial administration in conjunction with an opioid. (See "Interventional therapies for chronic pain".)

Although there is less published evidence of analgesic efficacy for both tizanidine, an oral drug approved as an antispasticity agent [42], and the parenteral drug dexmedetomidine [43,44], it is reasonable to consider all the alpha-2-adrenergic agonists as multipurpose analgesics. These effects presumably relate to activation of monoamine-dependent endogenous pain modulating pathways in the spinal cord and brain.

Alpha-2 agonists often produce somnolence and dry mouth and may cause hypotension, which is usually orthostatic. Medically ill patients often are predisposed to these toxicities, and based on clinical experience, these drugs usually are considered as second-line therapies for chronic pain that has not responded to trials of other adjuvant analgesics. Tizanidine has less hypotensive effect than clonidine and usually is considered first when pain is the target symptom [42,45,46]. Dosing with tizanidine may be initiated just at bedtime in an effort to provide hypnotic effects (table 2). If the drug is tolerated, dose escalation may proceed using two divided doses per day.

Cannabis and cannabinoids

Indications and benefit — A trial of non-inhaled medical cannabis or a cannabinoid pharmaceutical can be offered to patients with advanced cancer who have pain that has not adequately responded to opioids or other adjuvant analgesics. However, these agents, which may be considered multipurpose analgesics, appear to have limited analgesic efficacy and relatively high side effect liability, and also may raise concerns among patients or families related to the history of cannabis as a drug of abuse. Patients who place a relatively high value on small improvements in pain intensity, physical functioning, and sleep quality, and who have a willingness to accept a small to modest risk of harms, usually tolerable and self-limited, may seek a therapeutic trial, while those who place a greater value on avoiding treatment-related toxicity may decline.

"Marijuana," "medical marijuana," and "cannabis" refer to naturally grown plant materials that are not regulated by the US Food and Drug Administration (FDA) and are procured by patients from legal marijuana dispensaries or street suppliers. The primary psychoactive ingredient is tetrahydrocannabinol (THC).

The term "cannabinoids" refers to compounds derived from the cannabis plant, which contains more than 60 cannabinoids. Some of these compounds have pharmacologic effects, presumably mimicking the effects of endogenous cannabinoid compounds (the endocannabinoids) interacting with specific receptors in the nervous system and other tissues.

Although concern about the abuse potential of cannabinoid drugs has slowed their development (see "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects"), several cannabinoid-type drugs are commercially available, and others are under study:

The only United States approved cannabinoid (dronabinol) is approved only for chemotherapy-induced nausea and vomiting; a second oral agent, nabilone, is available in Canada and the United Kingdom, but was discontinued in the United States in 2019.

An oromucosal spray containing THC plus cannabidiol (CBD; and smaller concentrations of other compounds), called nabiximols (Sativex), is approved in more than 20 countries (but not in the United States) for treatment of spasticity related to multiple sclerosis. In Canada, the drug had also been approved as adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain, but this approval was withdrawn in January 2020 because of a lack of supporting data [47]. (See "Symptom management of multiple sclerosis in adults", section on 'Cannabinoids'.)

Although the evidence is limited and conflicting, there are data from controlled trials that suggest analgesic efficacy for cannabinoid drugs, as well as smoked cannabis [48-54]. Few studies have been conducted in cancer patients [51,55-57]. However, based on these data, the cannabinoids may be considered multipurpose analgesics for refractory pain in populations with advanced illness. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Cannabis and cannabinoids'.)

Multiple meta-analyses have been conducted on the analgesic effects of cannabis and cannabinoids:

Two early systematic reviews and two meta-analyses evaluating randomized trials of cannabis and cannabinoids found some evidence of efficacy for chronic pain, especially neuropathic pain [58-61]. However, all included trials studying different formulations in varied patient populations, and most of the trials included patients with neuropathic pain; very few were conducted in cancer patients. Not surprisingly, the results have been variable, with most concluding that cannabis might alleviate neuropathic pain in some patients (low-quality evidence) but there was insufficient evidence for other types of chronic pain, including pain related to cancer.

A later meta-analysis of five randomized controlled trials (n = 1442 participants, five trials studying nabiximols [56,57,62], and a sixth comparing THC or THC/CBD versus placebo [51]) in patients with cancer, all judged to be at low risk of bias, concluded that there was no difference between cannabinoids and placebo for the difference in the change in average numeric rating scale pain scores (mean difference -2.1, 95% CI -0.48 to 0.07) [63]. Cannabinoids had a higher risk of adverse events, especially somnolence (odds ratio [OR] 2.69, 95% CI 1.54-4.71) and dizziness (OR 1.58, 95% CI 0.99-2.51).

Most recently, a series of four linked systematic reviews summarizing the current body of evidence for benefits and harms, as well as patient values and preferences regarding oral medical cannabis or cannabinoids for chronic pain (both cancer- and noncancer-related) [64-67] came to the following conclusions:

Non-inhaled medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning, and sleep quality among patients with chronic pain [64]. Compared with placebo, non-inhaled medical cannabis results in a small increase in the proportion of patients experiencing at least the minimally important difference (MID) of 1 cm on a 10 cm visual analog scale (VAS) for pain, modelled risk difference of 10 percent (95% CI 5-15 percent) based on a weighted mean difference (WMD) in the VAS from baseline of -0.50 (95% CI -0.75 to -0.25, moderate certainty of evidence) [64]. Four of the 32 randomized trials included in this analysis enrolled patients with cancer-related pain, and all used nabiximols as the experimental group. Benefits were less certain in cancer-related pain (WMD -0.10, 95% CI -0.28 to 0.09) than in noncancer pain (WMD -0.63, 95% CI -0.96 to -0.29). The amount of heterogeneity between studies was higher in the noncancer setting (75 percent) as compared with chronic cancer-related pain (27 percent).

Non-inhaled medical cannabis also resulted in a very small improvement in physical functioning (4 percent modelled risk difference (0.1 to 8 percent) for achieving at least the MID of 10 points on a 100 point SF-36 physical functioning scale, WMD 1.67 points (0.03 to 3.31 points), high certainty of evidence), and a small improvement in sleep quality (6 percent modelled risk difference [2 to 9 percent] for achieving at least the MID of 1 cm on a 10 VAS sloop quality scale, WMD -0.35, 95% CI -0.55 to -0.14, high certainty of evidence).

There was moderate certainty of evidence that non-inhaled cannabis probably results in a small increased risk of transient cognitive impairment, drowsiness, impaired attention, and nausea; and high-certainty evidence showing a greater risk of dizziness.

In a separate analysis, there was very low-certainty evidence that adverse events are common among people living with chronic pain who use medical cannabis or cannabinoids, but few patients experience serious adverse events [67].

Another analysis concluded that there is low to very low certainty evidence that values towards medical cannabis among people living with chronic pain are highly variable, and high to moderate certainty evidence that patient's use of medical cannabis for chronic pain was influenced by both positive (eg, support from friends and family) and negative social factors (eg, stigma surrounding cannabis use) [65]. Many valued the effectiveness of medical cannabis for symptom management even when experiencing adverse events related to concentration, memory or fatigue. Reducing use of prescription medication was a motivating factor for use of medical cannabis, and concerns regarding addiction, losing control or acting strangely were disincentives.

However, a separate analysis concluded that the opioid-sparing effects of medical cannabis for chronic pain remain uncertain due to very low-certainty evidence [66].

These results led an international guideline expert panel to issue a weak recommendation to offer a trial of non-inhaled medical cannabis or cannabinoids, in addition to standard care and management (if not sufficient) in people living with chronic cancer or noncancer pain (figure 1) [68].

Choosing an agent for a therapeutic trial

Dronabinol – Until cannabinoid preparations become available and approved for pain the use of a cannabinoid for cancer pain must employ a drug that is marketed for purposes other than pain, specifically dronabinol (or nabilone, where available). If a therapeutic trial is offered, dronabinol usually is started at a dose of 2.5 mg once or twice daily and titrated. Nabilone should be started at 0.5 to 1 mg at night and titrated up to 3 mg twice daily, or higher if tolerated. Nabiximols oral spray should be initiated at no more than two sprays per day, evenly distributed over the course of the day. The use of smoked, vaporized, or ingested cannabis (marijuana) continues to be controversial.

Medicinal cannabis – Medical use of smoked, vaporized, or ingested cannabis is legal in several countries, including the Netherlands and Canada. However, cannabis use is still illegal in the United States at the federal level (which considers marijuana a schedule I controlled substance) but is legal in most states. Clinicians may not prescribe cannabis but the states that have legalized medical use may rely on clinician assessment to determine eligibility for treatment and recommended formulation and dose [69]. There are no randomized studies of inhaled cannabis for cancer related pain, although an individual patient data meta-analysis of five, randomized, double-blind, placebo-controlled trials [53,54,70-72] of inhaled whole-leaf cannabis for chronic neuropathic noncancer-related pain (n = 178 patients) concluded that the OR for more than a 30 percent reduction in subjective pain scores for inhaled cannabis versus placebo was 3.2 (95% credible interval [CRI] 1.59-7.24), and the number needed to treat to see benefit in one patient was 5.53 (95% CRI 3.35-13.7) [60].

Although severe or chronic pain accounts for over 90 percent of the qualifying conditions for use of medicinal cannabis among registered users in the states in which it is legal [73-76], its value for the treatment of chronic cancer pain remains uncertain. Some clinicians have embraced the approach, viewing the extant data and clinical anecdotes as sufficiently compelling to provide broad support. Other clinicians are hesitant, however. Given the heterogeneous legal status of marijuana, especially within the United States, the differences in cannabinoid concentrations across strains of cannabis and available products [77], the inability to stipulate, know, or titrate the dose taken by the patient, the general paucity of evidence-based information about efficacy and potential drug-drug interactions, and concerns about respiratory effects and cancer risk in cannabis smokers [55,78-83], clinicians may decide to recommend against its use, even in jurisdictions where it is legal. Given the state of the science and the sociopolitical complexities, each clinician must make his or her own decision while hopefully keeping an open mind. Should patients experience pain that is refractory to conventional therapies or report using and benefitting from cannabis, it is reasonable to accept a patient's decision to try medical cannabis and continue its use if it is helpful.

CBD oil – CBD (cannabidiol) is a naturally occurring molecule without psychoactive properties. It can be procured by patients from legal marijuana dispensaries, online companies, or street suppliers (CBD oil [nutraceutical]). An approved formulation of CBD oil (pharmaceutical) is now available in the United States as a purified product available by prescription (Epidiolex) and approved for treatment of some types of refractory epilepsy in children. (See "Dravet syndrome: Management and prognosis" and "Lennox-Gastaut syndrome".)

Although CBD oil (herbal) is used by patients as a nutraceutical for a variety of other conditions, there are few data on its benefits or risks in any type of cancer pain, and use cannot be recommended. A single phase II randomized double-blind placebo-controlled trial of CBD oil for relief of symptoms in advanced cancer concluded that CBD oil did not add value to the reduction in symptom distress (including pain) provided by specialist palliative care [84].

Adverse effects — The central nervous system effects of the cannabinoids and cannabis may provoke varied adverse effects, including drowsiness or somnolence, dizziness, fatigue, disorientation or confusion, mood change (eg, euphoria or dysphoria), loss of balance, and hallucinations [58,85]. Dry mouth may occur and some patients develop nausea and vomiting, which may be severe in some patients. Cardiovascular effects, including postural syncope and arrhythmias are also reported, and myocardial infarction has occurred, although the frequency with which these effects occur is unknown [86]. The long-term adverse effects of medical cannabis use are largely unknown, but low-strength evidence suggests that smoking marijuana is associated with cough, sputum production, and wheezing [81]. (See "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects".)

Chronic use of cannabis also has been associated with withdrawal symptoms after sudden cessation of use. These symptoms, such as anxiety, headache, and hypersomnia, could potentially manifest after hospital admission. (See "Cannabis withdrawal: Epidemiology, clinical features, diagnosis, and treatment".)

Topical therapies — A trial of a transdermal lidocaine patch is reasonable in patients who have localized, peripherally generated pain. Other commercially-available topical treatments that may be beneficial in specific circumstances include local anesthetic formulations (eg, eutectic mixture of local anesthetics [EMLA] cream for the pain of a needle stick or an incision), capsaicin for neuropathy-related pain, nonsteroidal anti-inflammatory drugs (NSAIDs) for local or locoregional pain; other drugs, such as TCAs, have been compounded for topical use.

A variety of topical therapies have been used to treat diverse pain syndromes and may be considered a multipurpose analgesic approach. Topical therapies have the potential to deliver analgesic compounds directly to the site that is presumably responsible, at least in part, for the persistent pain. The relative lack of systemic toxicity offers a therapeutic advantage that may be particularly relevant to the medically ill. Although topical analgesics have been used mostly for neuropathic pain, they have the potential for broader application. An overview of topical analgesics for treatment of superficial painful conditions is provided in the table (table 4).

Local anesthetics — The most widely used topical therapies for pain contain local anesthetics. Lidocaine 5% patches may be applied to treat focal or regional pain of all types; lidocaine gels and creams are less often used because they have to be reapplied two to four times per day, but they are less expensive.

The evidence to support benefit from topical lidocaine is relatively weak, however. A 2014 systematic review concluded that there is little evidence to support the use of topical lidocaine to treat neuropathic pain, but results from individual studies and clinical experience suggest that it can be effective in some patients [87]. Surveys of studies using relatively high concentrations of topical lidocaine gel suggest that a compound of this type can produce benefits for focal, peripherally generated pain, such as occurs in postherpetic neuralgia [88]. (See "Postherpetic neuralgia", section on 'Topical therapy for patients with milder symptoms' and "Pharmacologic management of chronic non-cancer pain in adults", section on 'Topical agents'.)

Although the current approved use for the lidocaine patch (based on clinical trials) is a 12-hours-per-day dosing regimen, some patients find that pain relief does not last 24 hours, and continuous application is common in the clinical setting. Multiple patches are often used together. There are limited data that indicate a high level of safety with four patches applied for 24 hours a day for up to 72 hours [89].

The most frequently reported adverse event from the lidocaine patch is mild to moderate skin irritation at the patch application site, which seems to be related to the vehicle rather than to lidocaine. There is only a remote risk of toxicity from systemic absorption of lidocaine, but it may be a concern in patients with impaired renal or hepatic function [90,91]. Cost may be prohibitive.

Lidocaine also is available in combination products. One such product is a lidocaine-menthol patch. Menthol is thought to contribute to the analgesic efficacy of the patches by dilating the blood vessels and causing a sensation of coldness followed by an analgesic effect. All patches are recommended to be left in place for up to 12 hours, and no information is available on continuous application.

Another combination product is a mixture of prilocaine and lidocaine, which is known as EMLA cream. EMLA cream is capable of penetrating the skin and producing a dense, local, cutaneous anesthesia [92]. This product and other similar formulations have been approved to prevent the pain of needle puncture or incision. In cancer patients who are having an invasive procedure, such as a lumbar puncture, or having a subcutaneous port accessed with a needle, application of a thin layer under an occlusive dressing is usually very effective though relatively expensive.

Capsaicin — Capsaicin, a naturally occurring constituent of the chili pepper, depletes substance P from the terminals of afferent C fibers. Topical application of a commercially available capsaicin cream or low-dose transdermal patch (strength varying from 0.025 to 0.1 percent), which are available over the counter in the United States, has yielded weak to moderate analgesic effects in controlled trials focusing on patients with various types of neuropathic and/or joint pain (table 4); few of these trials included patients with cancer-related neuropathic pain [93-96]. Burning at the application site, which is often transitory, is the major side effect and may lead to treatment discontinuation. Application three to four times daily for a period of at least a week is needed to determine benefit.

Capsaicin also is available in a high-concentration patch (8 percent capsaicin, Qutenza), which requires a prescription, and is approved for treatment of postherpetic neuralgia and painful diabetic peripheral neuropathy in the United States and for all types of peripheral neuropathic pain in the European Union. Efficacy was addressed in a year 2017 Cochrane review of eight placebo-controlled trials (2488 participants; four trials of postherpetic neuralgia, two of painful human immunodeficiency virus-related neuropathy, one of diabetic neuropathy, and one of patients with persistent pain following inguinal herniorrhaphy; no patient had cancer-related pain); six of the eight trials used 0.04% topical capsaicin as an "active" placebo) [97]. The authors concluded that high-concentration capsaicin generated more patients with moderate or substantial levels of pain relief than use of a much lower concentration of capsaicin, but that the quality of the evidence was moderate to very low. Local adverse events were common but not consistently reported.

High-concentration capsaicin patches are typically administered as a single 60-minute application. However, a single application for 30 minutes may be efficacious for several months, and treatment can be repeated [98]. Treatment must be administered by a health care professional, and patients are monitored for up to two hours after treatment. Eye and mucous membrane exposure must be avoided. To manage local pain from capsaicin application, the skin is pretreated with a local anesthetic such as topical lidocaine.

Anti-inflammatory and antidepressant drugs — Numerous anti-inflammatory drugs have been investigated for topical use. A diclofenac patch and gel are commercially available in the United States; others are available outside of the United States (table 4).

A 2017 Cochrane review concluded that there is overall strong evidence that these compounds are effective for acute musculoskeletal pain and low-quality evidence that they can help with chronic musculoskeletal pain [99]. Although there are no data on effectiveness as an adjuvant for treatment of cancer-related or cancer-treatment-related pain, evidence of safety and efficacy is sufficient to warrant a therapeutic trial in patients with small areas of local or locoregional pain of any cause. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Topical agents'.)

Evidence for the analgesic efficacy of topical TCAs is conflicting [100,101], but a cream containing one of these drugs may be tried local or regional pain. Topical doxepin is commercially available for the short-term management of pruritus and it may be considered for an analgesic trial. (See "Pruritus: Therapies for localized pruritus".)

Other topical drugs — Other drugs have been used empirically in specially compounded creams for use in patients with pain. The most popular are ketamine and gabapentin, but a variety of others are in use. At least one trial suggests potential benefit for a compounded topical gel containing baclofen, amitriptyline, and ketamine in patients with painful chemotherapy-induced peripheral neuropathy (CIPN) [102]. Supporting data overall are very meager or absent, however, a 2020 guideline from the American Society of Clinical Oncology on treatment for CIPN concluded that no recommendation may be made about the use of topical amitriptyline and ketamine with or without baclofen for this use [103]. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Topical treatments containing amitriptyline and ketamine with and without baclofen'.)

Botulinum toxin — Botulinum toxin type A injections have been used for treatment of refractory pain in migraine, trigeminal neuralgia, postherpetic neuralgia, and other focal pain syndromes. (See "Postherpetic neuralgia", section on 'Botulinum toxin' and "Chronic migraine", section on 'Second- and third-line agents' and "Trigeminal neuralgia", section on 'Alternatives and adjuncts to first-line therapy'.)

Emerging evidence suggests that botulinum toxin might also be effective for other types of otherwise refractory chronic pain [104], although the only data in cancer patients are in head and neck cancer patients with painful neck contracture after chemoradiation, paraneoplastic Raynaud phenomenon in a patient treated for lung cancer, and focal pain at the site of radiation or surgery [105-107].

PATIENTS WITH NEUROPATHIC PAIN — Neuropathic pain may be caused by the cancer (eg, radiculopathy from local tumor invasion), antineoplastic treatment (eg, chemotherapy-induced peripheral neuropathy [CIPN]), or by comorbidities such as diabetes. (See "Overview of cancer pain syndromes", section on 'Tumor-related neuropathic pain' and "Overview of cancer pain syndromes", section on 'Chemotherapy-related neuropathy'.)

Adjuvant analgesics are commonly considered for this indication and, with the sole exception of CIPN, best practices in the management of cancer-related neuropathic pain are generally extrapolated from guidelines developed for chronic noncancer conditions, such as diabetic painful neuropathy, postherpetic neuralgia, and others.

General principles

Timing and treatment selection – As noted above, there are no published data that inform the decision about the timing of adding an adjuvant analgesic to the pain control regimen therapy in patients with cancer-related pain, including neuropathic pain, and this remains a matter of clinical judgment. (See 'Integration into cancer pain management' above.)

As discussed in more detail below, the management of cancer survivors with neuropathic pain mirrors populations with chronic neuropathic pain unrelated to cancer. Trials of adjuvant analgesics are provided and opioid therapy is considered for those with refractory pain after a careful evaluation of potential benefits and risks.

In the setting of active cancer, some experts advocate a trial of an adjuvant analgesic for neuropathic pain only if the response to an opioid has been unsatisfactory, (ie, after an opioid has been titrated to optimize the balance between analgesia and side effects). Others advocate early use of adjuvant analgesics, either alone or in tandem with cautious opioid titration [108]. Evidence to guide the best approach is lacking. Although neuropathic pain may be relatively less responsive to opioids than other types of cancer-related pain, the outcome of an individual patient cannot be predicted and a favorable response to opioid-based analgesia is often possible. Given the acceptance of opioid therapy as the first line approach for moderate or severe pain related to active cancer, for most patients, we prefer to offer an opioid first and employ the adjuvant drugs to manage inadequate opioid responsiveness. (See "Assessment of cancer pain" and "Cancer pain management with opioids: Optimizing analgesia".)

The adjuvant analgesics usually selected for neuropathic pain include drugs categorized as multipurpose analgesics and drugs that are used selectively for neuropathic pain. A common approach first considers whether the extent of the pain permits use of a topical drug such as lidocaine at least initially. For systemic therapy, the usual first-line drug is one of the gabapentinoids (either gabapentin or pregabalin), unless the patient has a mood disorder that would be concurrently targeted by an analgesic antidepressant or the patient has a chemotherapy-induced painful neuropathy, in which the usual first-line systemic therapy is duloxetine.

Active cancer versus cancer survivors – The foregoing recommendation to optimize an opioid regimen before considering treatment with an adjuvant analgesic refers to the population with active cancer [109]. Neuropathic pain also occurs in cancer survivors with no active disease (eg, those with post-treatment neuropathic pain, such as with a postmastectomy pain syndrome, oxaliplatin-related chronic painful neuropathy). In this large group of patients, long-term opioid therapy for chronic pain is perceived to have a more limited role, one that mirrors the role of opioid therapy in chronic noncancer pain syndromes. (See "Postmastectomy pain syndrome: Risk reduction and management", section on 'Pharmacotherapy' and "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Specific interventions that are recommended'.)

Cancer survivors with chronic neuropathic pain typically receive trials of adjuvant analgesics, and opioids are only considered on a case-by-case basis, usually after other therapeutic trials have been ineffective. This more limited role reflects concern about the ongoing risks associated with opioid drugs and the need for careful long-term management of adverse effects related to both drug toxicities and abuse liability. (See "Prevention and management of side effects in patients receiving opioids for chronic pain" and "Cancer pain management: General principles and risk management for patients receiving opioids".)

A high degree of caution in the use of long-term opioid therapy is also warranted in some populations with limited or indolently growing neoplasms, whose pain syndromes may mirror those experienced by cancer survivors without active disease. A careful assessment of risk and benefit should always be performed, and a commitment to long-term opioid therapy should be justified by a favorable response and responsible drug-taking behavior.

Our suggested approach — The following represents our general approach to these patients:

Cancer-related neuropathic pain syndromes vary. Those associated with focal, local, or regional pain that may be amenable to a topical treatment (eg, focal chest pain due to painful intercostal mononeuropathy related to invasion of the chest wall by lung cancer) should be considered for a trial of topical lidocaine usually in combination with systemic analgesic therapy. In the context of active cancer, systemic analgesia usually involves a trial of an opioid and an orally-administered adjuvant analgesic is added if the opioid does not provide a favorable balance between analgesia and side effects. If the neuropathic pain is a post-treatment syndrome in a cancer survivor, systemic trials of adjuvant analgesics are the preferred starting point for systemic therapy and the addition of an opioid is considered on a case-by-case basis. (See 'General principles' above.)

If the pain syndrome is CIPN, duloxetine is a preferred first-line agent because of the statistically significant (albeit clinically modest) reduction in pain associated with this agent in CIPN. Specific recommendations are provided elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)

For all other neuropathic pain syndromes, we suggest one of the gabapentinoids, either gabapentin or pregabalin, rather than an analgesic antidepressant. Pregabalin may be preferred because dose titration is simpler. (See 'Gabapentin and pregabalin' below.)

However, if the neuropathic pain is associated with a depressed mood, we suggest an analgesic antidepressant rather than a gabapentinoid. For most patients we prefer a serotonin-norepinephrine reuptake inhibitor (SNRI) such as duloxetine. (See 'Antidepressants' below.)

The patient with advanced cancer and short prognosis also may be considered for a trial of a glucocorticoid (eg, dexamethasone 0.75 to 1.5 mg once or twice daily) particularly if pain is accompanied by other symptoms such as nausea.

Patients who don't respond to the initial drug trial may be considered for trials of the alternative gabapentinoid or alternative analgesic antidepressants. Some experts follow an ineffective trial of a drug by choosing the next drug from a different class (eg, trying a gabapentinoid if an antidepressant is not effective), but there is no evidence to support this practice. Another option is to combine a gabapentinoid with a low-dose antidepressant (eg, desipramine). Clinicians should avoid prescribing combinations of antidepressants as this can induce the serotonin syndrome. (See "Serotonin syndrome (serotonin toxicity)".)

If therapeutic trials of the gabapentinoids and the analgesic antidepressants prove unsatisfactory, sequential trials of other adjuvant drugs can be tried, although there is very little evidence to guide treatment selection and recommendations reflect a limited literature and clinical experience. The preferred alternatives are the anticonvulsants, oxcarbazepine or lacosamide, or the alpha-2 adrenergic agonist, tizanidine. A brief intravenous infusion of lidocaine, typically 2 to 4 mg/kg infused over 20 to 30 minutes in a monitored setting, has been used for severe neuropathic pain and can result in prompt pain reduction so that other strategies can be implemented more gradually. (See 'Sodium channel blockers' below.)

A trial of non-inhaled medical cannabis or cannabinoids can be offered to patients with advanced cancer and neuropathic pain that has not adequately responded to opioids or other alternative adjuvant analgesics. (See 'Cannabis and cannabinoids' above.)

For patients with refractory focal pain, botulinum toxin injection is another option. (See 'Botulinum toxin' above.)

Treatment-refractory neuropathic pain may respond to ketamine, although the available evidence is limited. (See 'Ketamine and other NMDA receptor antagonists' below.)

Individual treatments

Antidepressants — As noted above, the most useful analgesic antidepressants are the SNRIs (with duloxetine having the most robust evidence, at least for CIPN) and the secondary amine tricyclic antidepressant (TCA) compounds (eg, desipramine). Evidence of analgesic efficacy for a variety of types of chronic pain has been demonstrated in randomized controlled trials and meta-analyses. (See 'Selection of agent and dose' above.)

Positive results with duloxetine in a single, randomized, double-blind, placebo-controlled crossover trial conducted in patients with painful CIPN after treatment with taxane- or platinum-containing chemotherapy support the view that in this setting, duloxetine is an appropriate first-line agent, particularly in view of a negative gabapentin trial in this setting [37] and no other randomized trials showing benefit for any other strategies for CIPN, painful or not. However, additional data will be needed to establish the superiority of duloxetine or any other antidepressant over the gabapentinoids in these patients and to establish the efficacy of duloxetine in patients with CIPN from other drugs, such as vinca alkaloids. Specific recommendations in this setting are provided elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Duloxetine' and "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Gabapentinoids'.)

Most experts also consider the analgesic antidepressants to be preferred first-line treatments for neuropathic pain that is associated with a significant depressed mood, notwithstanding the lack of trials comparing antidepressants with other strategies (such as anticonvulsants) in this setting. For most patients, an SNRI such as duloxetine is preferred over other antidepressants such as a TCA. (See 'Analgesic antidepressants' above.)

For nondepressed patients with neuropathic pain who achieve meaningful, but insufficient analgesia with a gabapentinoid, an analgesic antidepressant may be added (eg, low-dose desipramine) may be added if the risks are acceptable.

It is important to emphasize that these conclusions are not evidence-based and that additional trials are needed. In particular, few data have directly compared antidepressants versus anticonvulsants in any group of patients with cancer-related neuropathic pain, precluding robust evidence-based recommendations:

A systematic review of the effectiveness of antiseizure medications or antidepressants added to opioids for neuropathic pain from cancer, described above, concluded that benefit from any adjuvant was modest and much less than that seen in patients with noncancer neuropathic pain; benefit was strongest for gabapentin and was counterbalanced by an increase in adverse events [110]. (See 'Gabapentin and pregabalin' below.)

A second systematic literature review concluded that the absolute benefit for all adjuvant analgesics, including antidepressants, greatly outweighed the absolute risk for harm, but that all studies had low methodologic quality, precluding any conclusions about the relative effect sizes of antidepressants relative to any other medication groups, including gabapentinoids [111].

Anticonvulsants — The anticonvulsants represent a diverse group of drugs that vary in mechanisms and clinical effects (table 1 and table 2). Two of the drugs in this group (the gabapentinoids gabapentin and pregabalin) are approved in the United States for treatment of various painful conditions and are considered the first-line approach for patients without comorbid depression who have neuropathic cancer pain other than painful neuropathy due to chemotherapy (an evidence-based approach for taxane or platinum-based chemotherapy-induced painful neuropathy). (See 'Antidepressants' above.)

Gabapentin and pregabalin

Mechanism of action – The gabapentinoids act by binding to the alpha-2-delta protein modulator of the N-type voltage-gated calcium channel. Binding to this protein reduces calcium influx into the neuron and lessens the likelihood of depolarization.

Side effects and precautions – Unlike all other anticonvulsants, gabapentin and pregabalin are not metabolized in the liver, and they have few drug-drug interactions, with the important exception of enhancing the central nervous system (CNS) depressive effects of other centrally-acting drugs. This includes the opioids, and there is an increased risk of oversedation or a serious adverse consequence (including death) when gabapentin or pregabalin is added to an opioid regimen [112,113]. The risk is highest in cancer patients with multiple comorbidities who are taking multiple centrally-acting drugs, and it must be recognized and carefully monitored.

Given this potential for CNS depression, gabapentinoids should be administered cautiously to patients who are receiving centrally-acting drugs with sedative effects, especially opioid drugs. In 2020, the US Food and Drug Administration (FDA) mandated revisions to the labeling regarding the risk of severe and life-threatening respiratory depression with use of gabapentinoids, particularly in combination with CNS depressants (eg, opioids), in those with underlying respiratory disease and in older adults [114]. (See "Prevention and management of side effects in patients receiving opioids for chronic pain", section on 'Somnolence and mental clouding'.)

Both of the gabapentinoids are excreted by the kidneys, which necessitates dose reduction in the setting of renal impairment. Their main side effects are mental clouding, dizziness, and somnolence; edema and weight gain are less common.

EfficacyGabapentin and pregabalin have been extensively studied for diverse types of neuropathic pain, particularly postherpetic neuralgia and painful diabetic neuropathy. (See "Postherpetic neuralgia", section on 'Gabapentinoids for most patients with moderate or severe pain' and "Management of diabetic neuropathy", section on 'Pain management'.)

Efficacy is also suggested for patients with neuropathic pain related to cancer or its treatment, although fewer data are available:

In three, small, randomized, placebo-controlled trials involving populations of opioid-treated patients with cancer-related neuropathic pain, the addition of gabapentin or pregabalin was significantly better than placebo at improving neuropathic pain and dysesthesias [115-117]; one of these trials directly compared gabapentin with pregabalin and is discussed in more detail below [116].

Another placebo-controlled randomized trial of gabapentin for painful CIPN failed to show any benefit for gabapentin. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Gabapentinoids'.)

A benefit for pregabalin alone (ie, without opioids) in the treatment of radiation therapy-related neuropathic pain was also suggested in a randomized, placebo-controlled, double-blind trial of 128 head and neck cancer survivors [118]. Patients treated with dose-adjusted pregabalin (16 weeks of treatment, starting at 75 mg daily and increasing up to 300 mg twice daily depending on pain relief and tolerability) had a significant reduction in their mean pain intensity (pain intensity reduction 2.44 versus 1.58 on an 11-point numeric rating scale, adjusted mean difference 0.87, 95% CI 0.03-1.44). Patients receiving pregabalin also had better mood states and a higher quality of life, and fewer required rescue pain medication (13 versus 41 percent) during the study period.

A systematic review of the effectiveness of antiseizure medications or antidepressants added to opioids for neuropathic pain from cancer concluded that benefit from any adjuvant was modest and much less than that seen in patients with noncancer neuropathic pain; the effect was strongest for gabapentin but was counterbalanced by an increase in adverse events [110].

By contrast, a second systematic literature review of the evidence for pharmacologic treatment of neuropathic cancer pain concluded that the absolute benefit for all agents (antidepressants, anticonvulsants) greatly outweighed the absolute risk for harm, but that all studies had low methodologic quality, precluding conclusions about the relative effect sizes of the different medication groups [111].

Choice of agent and dose — If available, and not prohibitively expensive for the patient, pregabalin may be preferred for an initial trial of a gabapentinoid because dose adjustments are simpler than they are for gabapentin.

A typical starting dose of pregabalin is 50 to 75 mg twice daily. Further escalation to the usual effective dose of 150 to 300 mg twice daily typically is accomplished in two to three steps over one to two weeks. In medically frail cancer patients and those with significantly impaired kidney function, the starting dose should be reduced to 25 mg per day, and titration is slower.

Gabapentin is often initiated at a dose of 300 mg per day (or 100 mg per day in the medically frail or renally impaired). The dose is doubled and administered as two divided doses per day after a few days. The dose is then gradually escalated every few days while monitoring analgesia and side effects. If pain relief does not occur, in the absence of an analgesic ceiling (dose escalation does not yield more analgesia) and adverse effects, escalation can extend to 3600 mg per day, administered in two to three divided doses. Occasional patients benefit from even higher doses. If possible, it is preferable to taper these drugs prior to discontinuation.

There are important pharmacokinetic differences between gabapentin and pregabalin that may impact choice of treatment:

Absorption and entry of gabapentin into the CNS is facilitated by a saturable transporter in the small bowel and CNS. At relatively higher doses (approximately 1800 mg per day, but could be higher or lower in individual cases (table 2)), the kinetics become nonlinear and there is less complete absorption with each dose increment. These saturable kinetics mean that gabapentin has a pharmacokinetic "ceiling," which coexists with a possible pharmacodynamic "ceiling" of the type that is observed with all adjuvant analgesics (ie, at some point, a maximum effect is reached and further dose increments provide no additional benefit).

By contrast, absorption of pregabalin is not dependent on a saturable transport mechanism, and this drug only has the unpredictable pharmacodynamic ceiling. This linear pharmacokinetic profile simplifies dosing of pregabalin compared with gabapentin.

From an efficacy standpoint, studies suggest that individual patients may be responders to gabapentin, pregabalin, both, or neither [119]. The superiority of one drug over the other was directly tested in a double-blind trial that randomly assigned 120 patients with cancer and severe neuropathic pain to gabapentin (900 mg daily for one week, followed by 1200 mg daily for one week, then 1800 mg daily), pregabalin (150 mg daily for one week, followed by 300 mg daily for one week, then 600 mg daily), amitriptyline (50 mg daily for one week, followed by 75 mg per day for one week, then 100 mg daily at bedtime), or placebo [116]. The primary outcome measure was the global intensity of pain as measured on a 100 mm Visual Analog Scale (VAS). By week 4, the mean VAS score with pregabalin was significantly less than that with gabapentin, and the percentage of patients requiring rescue morphine in the placebo, amitriptyline, gabapentin, and pregabalin groups was significantly different (100, 57, 33, and 17 percent, respectively).

While this study suggests that pregabalin may have superior efficacy, study limitations (ie, unclear methods for randomization, blinding or statistical analysis, and the primary endpoint analysis was not conducted in an "intention to treat" population) preclude definitive conclusions. In addition, the drugs were tested at doses that may not be fairly compared; the initial dose of pregabalin was relatively high, while the top dose of gabapentin would not be considered relatively high for this drug. For all of these reasons, it cannot be concluded that pregabalin is superior to gabapentin for treatment of neuropathic pain.

Other anticonvulsants — The non-gabapentinoid anticonvulsants have diverse mechanisms and data pertaining to analgesic efficacy for neuropathic pain are limited. A small number of these drugs (oxcarbazepine, lacosamide) may be considered for a trial in patients who have not responded satisfactorily to the gabapentinoids and other preferred agents, such as the antidepressants [120].

Older anticonvulsants, such as carbamazepine, valproate, and phenytoin, are perceived as having potential analgesic effects based on trials performed, in some cases, many decades ago. Systematic reviews have concluded that the evidence for any of these drugs in neuropathic pain is low quality [110,111,121,122]. The newer anticonvulsants have a better adverse effect profile, but again, have very limited evidence of efficacy.

Oxcarbazepine – Oxcarbazepine is a metabolite of carbamazepine that has similar anticonvulsant properties and a safer pharmacologic profile. Although the quality of the evidence is limited [123], it has been shown to be analgesic in trigeminal neuralgia and several other types of peripheral neuropathic pain [124]. A trial of this drug may be considered after trials of the gabapentinoids and perhaps one or two of the analgesic antidepressants have proven unhelpful.

Lacosamide – Lacosamide, a relatively new anticonvulsant, is a sodium channel modulator with a unique mechanism of action. A Cochrane review concluded that lacosamide has limited efficacy in treatment of painful diabetic neuropathy [125]; there are no data in patients with cancer-related pain. Based on these limited efficacy data, this agent also could be considered among those that are potentially useful for treatment of refractory neuropathic pain.

Lamotrigine – Lamotrigine has been effective in studies of central pain, trigeminal neuralgia, painful human immunodeficiency virus polyneuropathy, and postherpetic neuralgia, but it has not been analgesic in other trials, including one conducted in patients with painful CIPN [126]. This drug is associated with a small risk of severe cutaneous hypersensitivity, which is relatively higher in younger patients. It should not be used in patients under the age of 15, and slow titration of the dose from a low initial dose is necessary to reduce the risk of hypersensitivity. Given the limited evidence of efficacy, the need for slow titration, and the risk of severe cutaneous hypersensitivity, this drug is not a preferred second-line agent for neuropathic pain and usually is considered only after neuropathic pain has proved to be refractory to other preferred drugs.

Topiramate – Topiramate, an effective drug for prevention of episodic migraine, has been variably effective in studies of neuropathic pain. Although anecdotal experience suggests that some patients with cancer and neuropathic pain derive benefit, it is generally considered only after other second-line drugs have been proved ineffective [127,128]. (See "Preventive treatment of episodic migraine in adults", section on 'Topiramate'.)

Others – As noted, the data supporting the analgesic efficacy of valproate and phenytoin are limited [129,130]. Although these drugs may be considered for trials in patients with intractable neuropathic pain, conventional practice in countries that have access to newer agents relegates them to trials after other anticonvulsants have been demonstrated to be ineffective.

There is no evidence to support the analgesic efficacy of levetiracetam, zonisamide, and tiagabine, and in the absence of additional data, these drugs usually are not considered unless others are not available.

Clonazepam is a benzodiazepine. Very meager data support analgesic efficacy in patients with neuropathic pain [131]. Its anxiolytic effects may be favorable, however, and a trial is sometimes considered in the patient with refractory neuropathic pain associated with anxiety.

Other drugs — Patients who do not respond favorably to trials of the gabapentinoids and analgesic antidepressants may be considered for trials of other drugs categorized as multipurpose adjuvant analgesics. A trial of an alpha-2 agonist, such as tizanidine, or a trial of a cannabinoid, such as dronabinol, might be considered. (See 'Alpha-2 adrenergic agonists' above and 'Cannabis and cannabinoids' above.)

Topical agents (starting with local anesthetic formulations such as a lidocaine patch ) should always be considered for an early trial when neuropathic pain is focal or regional [132]. (See 'Topical therapies' above and "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Topical treatments containing amitriptyline and ketamine with and without baclofen'.)

Other drug classes play a far less prominent role in the clinical strategy for cancer-related neuropathic pain. Patients with advanced illness and a short prognosis could be considered for a trial of a low-dose glucocorticoid (see 'Glucocorticoids' above). Occasional patients with refractory neuropathic pain who have not responded to other drugs may be considered for trials of one or more of these uncommon treatments based on very limited data and anecdotal experience.

Sodium channel blockers — Blockade of sodium channels has been recognized as an analgesic mechanism for decades, and the potential role of the new sodium channel modulator lacosamide was mentioned above. (See 'Other anticonvulsants' above.)

Treatment approaches using older sodium channel blockers include oral therapy with antiarrhythmic drugs, such as mexiletine or tocainide, or parenteral therapy, usually with lidocaine. The analgesic effects and generally favorable safety profile of these drugs are strongly supported by the literature [133,134]; the usual side effects are dizziness, nausea, and fatigue.

The use of a brief intravenous infusion of lidocaine, typically 2 to 4 mg/kg infused over 20 to 30 minutes in a monitored setting, can be beneficial in the context of very severe neuropathic because of its potential for rapid onset relief. If available, it can be used in the hope of gaining time so that other strategies can be implemented more gradually.

Ketamine and other NMDA receptor antagonists — Ketamine is used by specialists in palliative medicine to address refractory pain at the end of life [135,136]. Anecdotally, treatment-refractory pain, usually neuropathic, earlier in the course of illness also is considered a potential indication for ketamine, although the available evidence is limited.

Ketamine

Mechanism of action – The N-methyl-D-aspartate (NMDA) receptor is involved in both the sensitization of central neurons and the functioning of the opioid receptor, and there is evidence that one of the commercially available NMDA receptor antagonists, ketamine, has analgesic properties [137].

Efficacy – Many experts believe that ketamine at subanesthetic doses may be useful as a brief infusion for treatment of severe pain [135,136], or as a more prolonged infusion or oral therapy in the context of refractory pain associated with advanced illness [138]. The evidence to support benefit of ketamine as an adjuvant to opioid therapy is quite limited, however [139-145]. A 2017 Cochrane review of three of these trials (the rest were excluded because of methodologic problems or an extremely small number of patients completing the study) [139,141,144] concluded that the evidence was insufficient to assess the benefits and harms of ketamine as an adjuvant to opioids for the relief of refractory cancer pain [146].

Nevertheless, use of parenteral ketamine for chronic pain is supported in consensus guidelines from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists [147], and ketamine continues to be used by specialists in palliative medicine to address refractory pain at the end of life [135,136]. Anecdotally, treatment-refractory pain, usually neuropathic, earlier in the course of illness also is considered a potential indication.

Side effects and precautions – The side effect profile of ketamine, particularly psychotomimetic effects (including symptoms of dissociation, hallucinations, and delirium), can be problematic [148-150], and as a result, the most common use is for short-term therapy in a monitored setting. Based upon anecdotal observations that treatment with a benzodiazepine, such as lorazepam, or a neuroleptic, such as haloperidol [151], reduces the risk of psychotomimetic effects from ketamine, most practitioners co-administer one of these drugs prior to the start of the infusion and repeatedly during longer-term treatment. Gradual dose titration of ketamine may also reduce the incidence of psychotomimetic effects [152].

Route of delivery and doseKetamine may be delivered by subcutaneous or intravenous continuous infusion, brief infusion, or repeated bolus, or by the oral route:

-Brief infusion (eg, 100 mg per day, escalating by 100 mg per day increments, for two to five days) has been termed "burst" therapy, and may be used to manage episodes of severe pain [135,153]. However, this approach should be used cautiously given the risk of adverse effects with rapid dose escalation.

-Continuous infusion protocols may start with a loading bolus (eg, 0.1 to 0.5 mg/kg), followed by 0.05 to 0.2 mg/kg per hour [148,154]. The rate can be increased every few hours if pain relief is inadequate and side effects are tolerable. An alternative approach starts with 50 to 100 mg per day, irrespective of weight, with a daily dose increase by 25 to 50 percent, depending on effects.

-Oral ketamine can be started at 10 to 25 mg three or four times daily and then up-titrated until benefit or side effects emerge. In one retrospective survey, the mean effective total daily oral dose was 2 mg/kg [155].

Others – Other NMDA receptor antagonists, such as memantine, amantadine, and dextromethorphan, have been studied in neuropathic pain states, with mixed results [156]. They are rarely considered for trials in cancer-related neuropathic pain that has not responded to other agents.

GABA receptor modulators — Gamma-aminobutyric acid (GABA) receptor modulators include the benzodiazepines, which bind to the GABAA receptor subtype, and baclofen, which binds to the GABAB receptor subtype.

Benzodiazepines potentiate inhibitory effects of endogenous presynaptic GABA. As noted previously, the only benzodiazepine that is used for neuropathic pain is clonazepam, and this use is based on anecdotal observations. (See 'Other anticonvulsants' above.)

Baclofen reduces the release of excitatory neurotransmitters by binding to the GABAB presynaptic receptors within the brain stem, dorsal horn of the spinal cord, and other CNS sites. Baclofen is effective for the treatment of spasticity and also has established efficacy in trigeminal neuralgia. It has been used anecdotally for neuropathic pain of other types, including cancer pain [157]. A low starting dose of 5 mg twice daily can be gradually escalated to doses that may exceed 200 mg per day in some patients. (See "Trigeminal neuralgia", section on 'Alternatives and adjuncts to first-line therapy'.)

Recommendations of expert groups — Our recommendation for management of neuropathic pain in cancer patients are consistent with those of expert groups:

Year 2007 recommendations for treatment of neuropathic pain (including that related to cancer or secondary to chemotherapy) are available from the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (IASP) [108]. A stepwise approach to assessment and treatment is recommended in the IASP guidelines and is relevant to neuropathic cancer pain:

Assess the pain and establish the likely neuropathic etiology. The assessment should include identification of relevant comorbidities that may be impacted by treatment of neuropathic pain or require modifications in the initial treatment regimen. (See "Assessment of cancer pain".)

Initiate antineoplastic therapy for the disease causing the neuropathy, if applicable.

Initiate symptom treatment for the painful neuropathy. Recommended first-line treatments include certain antidepressants (ie, TCAs and SNRIs), gabapentinoids, and topical lidocaine. Opioid analgesics and tramadol are recommended generally as second-line treatments that can be considered for first-line use in select clinical circumstances.

Guidelines from the National Comprehensive Cancer Network [158] and the European Association for Palliative Care [159] broadly concur with the IASP guidelines, suggesting that antidepressants or anticonvulsants are the preferred first-line coanalgesics for treatment of cancer-related neuropathic pain, either alone, or in combination with opioids in patients whose pain is only partially responsive to opioids.

Updated 2020 guidelines from the American Society of Clinical Oncology suggest duloxetine for initial treatment of painful CIPN [103]. They did not limit this recommendation to taxane and platinum-related neuropathy. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Duloxetine'.)

PATIENTS WITH BONE PAIN — Bone is the most common pain-sensitive structure affected by cancer. The assessment of a patient with new bone pain may suggest the presence of a primary bone tumor or bone metastases, for which local treatments such as radiation therapy, kyphoplasty, or surgery, may be needed. (See "Assessment of cancer pain" and "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults" and "Radiation therapy for the management of painful bone metastases" and "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma" and "Assessment of cancer pain", section on 'Etiology'.)

The majority of patients with cancer-related bone pain require analgesia, and they are usually managed with a combined approach, utilizing nonsteroidal anti-inflammatory drugs (NSAIDs), unless they have a specific contraindication to use of these agents, plus an opioid, with or without an adjuvant analgesic used specifically for bone pain. (See "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs", section on 'Indications and contraindications'.)

Adjuvant analgesics to consider in this setting include osteoclast inhibitors (bisphosphonates, denosumab) and bone-seeking radiopharmaceuticals (table 1), glucocorticoids are usually reserved for patients with advanced illness and limited prognosis. (See 'Indications' above.)

The following represents our general approach to these patients:

Osteoclast inhibitors are indicated, in conjunction with an opioid, for patients with symptomatic bone metastases from a variety of cancers. These drugs prevent skeletal-related events, improve quality of life, and can improve bone pain, although their analgesic effects are only modest. (See 'Osteoclast inhibitors' below.)

Use of bone-targeted radiopharmaceuticals, such as radium-223, is typically reserved for the patient with multifocal bone pain that is refractory to other treatment. The majority of the data on efficacy are in patients with metastatic prostate cancer. (See 'Bone-targeted radiopharmaceuticals' below.)

Glucocorticoids may be useful in patients with opioid-refractory bone pain. As noted, some experts try a low-dose regimen to address pain and concurrent symptoms (eg, fatigue, nausea, and dysphoria) when the cancer is advanced and prognosis is limited. These drugs also may be considered for short-term treatment, especially in patients with a "pain crisis," which is defined as severe and escalating pain that is not responding sufficiently to an opioid. (See 'Choice of agent and dose' above.)

Osteoclast inhibitors — For patients with metastatic bone disease, bisphosphonates and denosumab prevent skeletal-related events, including fracture, and they may also improve pain and quality of life. Bisphosphonates act by directly inhibiting osteoclast activity, stimulating osteoblasts to produce osteoclast-inhibiting factor, and causing osteoclast apoptosis. Osteoclast inhibition can also be achieved by targeting the receptor activator of nuclear factor kappa B ligand, a key component in the pathway for osteoclast formation and activation. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Efficacy and dosing considerations for individual agents'.)

As adjuvant agents, there is evidence to support the analgesic potential of all osteoclast inhibitors, although benefit seems modest, particularly in the setting of metastatic non-small cell lung cancer (NSCLC) (see "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Impact on quality of life'):

In a Cochrane review, a significant improvement in bone pain was reported after receiving a bisphosphonate in patients with bone metastases from breast cancer in 6 of 11 studies [160].

In at least one trial, intravenous ibandronate was as efficacious as a single fraction of radiation therapy for treatment of localized bone pain from metastatic disease in males with prostate cancer [161].

On the other hand, a systematic review of bone-targeted agents in NSCLC concluded that the evidence for an analgesic effect of bisphosphonates or denosumab in patients with bone metastases was very weak [162].

Several reports note a modest but significant advantage for denosumab over zoledronic acid in terms of analgesic effect:

One randomized trial comparing zoledronic acid with denosumab in 2046 patients with bone metastases from breast cancer specifically reported endpoints related to bone pain and quality of life [163,164]. Compared with zoledronic acid, fewer patients receiving denosumab who had no or mild pain at baseline progressed to moderate or severe pain (although the absolute difference was only 5 percent), there was an almost-four-month-longer delay in the median time to pain worsening to moderate or severe, and fewer shifted from no or low analgesic use to strong analgesic use. At the majority of time points, fewer denosumab-treated patients experienced a meaningful worsening of pain severity (≥2 point increase from baseline), although the difference was modest (absolute difference 3 percent) [163]. In addition, 10 percent more denosumab-treated patients had a clinically meaningful improvement in health-related quality of life relative to zoledronic-acid-treated patients, regardless of baseline pain levels [164]. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Efficacy'.)

Other data are available from an integrated analysis of pain outcomes [165] with denosumab versus zoledronic acid derived from the original report of the above mentioned trial [166] and two other phase III trials in patients with bone metastases from castration-resistant prostate cancer or other solid tumors, excluding multiple myeloma [167,168]. Treatment with either drug was associated with improvements in pain outcomes. Denosumab significantly delayed the time to increase in pain interference overall (11.1 versus 9.3 months) and the time to pain interference with activity (8.3 versus 7.4 months, hazard ratio 0.9, p = 0.009). Furthermore, fewer patients receiving denosumab shifted to using a strong opioid (as compared with no analgesic, a nonopioid analgesic, or a weak opioid; 7.7 versus 9.1 percent). Additionally, treatment with denosumab compared with zoledronic acid reduced the risk of and delayed the time to development of moderate or severe pain in patients both with (5.7 versus 3.9 months) and without a prior skeletal-related event (6.7 versus 4.8 months).

The choice of one agent over another for patients with bone metastases is based on many factors, including cost (which is higher for denosumab). However, one advantage of denosumab over zoledronic acid is that it is a quick monthly subcutaneous injection and not a prolonged intravenous infusion. On the other hand, for many patients the dosing interval for zoledronic acid can be extended to every three months rather than monthly, increasing convenience and decreasing cost. These issues are all addressed in detail elsewhere. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Efficacy and dosing considerations for individual agents'.)

Although generally well tolerated, bisphosphonates are associated with some potentially serious side effects, including impaired renal function, hypocalcemia, osteonecrosis of the jaw, an increased risk of atypical femur fractures during prolonged therapy, and severe (and occasionally debilitating) bone, joint, and/or muscle pain. Some of the same side effects are shared by denosumab (ie, osteonecrosis of the jaw, hypocalcemia and other electrolyte abnormalities), although impairment of renal function has not been seen. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

Regardless of the agent chosen, given the modest analgesic effects of osteoclast inhibitors, in general, they should not be used alone for management of pain from bone metastases [169]. (See "Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors", section on 'General approach to the patient'.)

Bone-targeted radiopharmaceuticals — Alpha- and beta-emitting radiopharmaceuticals (radium-223, strontium-89, and samarium-153) link a short-lived radiation source to a bone-seeking molecule. Once injected, the drug is taken up at the site of bone metastases and delivers radiation locally. Myelosuppression, which has been a particular concern with strontium-89, is less of a concern with radium-223, an alpha emitter.

Bone-targeted radiopharmaceuticals represent a useful treatment for multifocal bone pain, but treatment requires special skills and facilities. These agents have been used most often for males with metastatic prostate cancer; their use is discussed in more detail elsewhere. (See "Bone metastases in advanced prostate cancer: Management", section on 'Bone-targeted radioisotopes'.)

Glucocorticoids — The benefit of glucocorticoids as multipurpose analgesics is discussed above. (See 'Glucocorticoids' above.)

A short course of glucocorticoids (eg, oral dexamethasone 8 mg once daily from days 1 to 5) may also be useful to prevent the bone flare during radiation therapy for treatment of painful bone metastases [170], although concerns over side effects such as insomnia and hyperglycemia have tempered enthusiasm for this approach This subject is addressed in detail separately. (See "Radiation therapy for the management of painful bone metastases", section on 'Time course of relief and incidence of pain flare'.)

PATIENTS WITH MALIGNANT BOWEL OBSTRUCTION — Bowel obstruction is a well-recognized complication in patients with advanced intra-abdominal or pelvic tumors. Most of these patients are inoperable, and their survival is generally short. Some cases may be amenable to placement of a self-expanding metal stent. (See "Enteral stents for the management of malignant colorectal obstruction".)

For patients with inoperable intestinal obstruction who are not appropriate for a stent, decompression of gastric contents can also be achieved through placement of a percutaneous gastrostomy tube. However, these procedures provide only incomplete relief of distressing symptoms, and the ongoing presence of these tubes can be uncomfortable and distressing for the patient and his or her caregivers. (See "Palliative care of bowel obstruction in cancer patients", section on 'Patients who are not surgical candidates'.)

More recently, medical management of inoperable patients has focused on adequate control of pain, distention, and vomiting using hydration, opioids, and adjuvant medications that may reduce symptoms by lessening peritumoral edema (glucocorticoids) and diminishing intraluminal secretions and peristaltic movements (anticholinergic agents and octreotide). The use of these agents as adjuvant analgesics in this situation is discussed in detail elsewhere. (See "Palliative care of bowel obstruction in cancer patients", section on 'Pharmacologic management'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Palliative care" and "Society guideline links: Neuropathic pain" and "Society guideline links: Cancer pain".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Managing pain when you have cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

General concepts

Adjuvant analgesics (coanalgesics) are drugs that have a clinical use other than pain but are used as analgesics in selected circumstances particularly when a patient is poorly responsive to opioids. The available agents are categorized on the basis of how they are used in clinical practice (table 1). (See 'Available agents and dose ranges' above.)

There are no published data that inform the decision about the timing of adjuvant analgesic therapy in patients with cancer-related pain. In contrast to patients with active cancer, in whom adjuvant analgesics may be added to the regimen for chronic pain that is poorly responsive to opioids, cancer survivors with chronic (typically neuropathic) pain usually receive an initial trial of an adjuvant analgesics, and opioids are only considered on a case-by-case basis, for refractory pain. This more limited role reflects concern about the ongoing risks associated with opioid drugs and the need for careful long-term management of adverse effects related to both drug toxicities and abuse. (See 'Integration into cancer pain management' above.)

Chronic pain that is not predominantly neuropathic, or related to bone metastases or malignant bowel obstruction

Patients with focal peripherally generated pain – A trial of topical therapy, beginning with a transdermal lidocaine patch, can be offered to patients who have focal, peripherally generated pain. (See 'Topical therapies' above.)

Patients with more generalized pain – In the setting of active cancer, a patient with chronic cancer pain that is not predominantly neuropathic or related to bone metastases or bowel obstruction should be considered for a trial of an analgesic antidepressant. Particularly for the patient who also has a depressed mood, we suggest an early trial of an analgesic antidepressant rather than a different adjuvant analgesic (Grade 2C). For most patients, we prefer duloxetine. If duloxetine is unavailable or poorly tolerated, our preferred alternative analgesic antidepressants include a different serotonin-norepinephrine reuptake inhibitor (SNRI) or a secondary tricyclic drug, such as desipramine. A trial of bupropion is reasonable if cancer pain is complicated by fatigue or somnolence, but the drug should be avoided in patients at risk for seizures. (See 'Analgesic antidepressants' above.)

Other options – Other options are alternatives for patients without depressed mood or second-line options that can be tried based on comorbidities and patient preference:

-Glucocorticoids can be useful in the treatment of a variety of types of cancer pain. Because of this potential for toxicity, a careful risk-to-benefit analysis is warranted whenever a glucocorticoid is being considered for pain management, which considers the availability of other treatments, the planned duration of treatment, other symptoms, treatment context, and life expectancy. (See 'Glucocorticoids' above.)

-A trial of non-inhaled medical cannabis or cannabinoids can be offered to patients with advanced cancer and refractory pain. Patients who place a relatively high value on small or very small improvements in self-reported pain intensity, physical functioning, and sleep quality, and a willingness to accept a small to modest risk of mostly self-limited and transient harms may choose a therapeutic trial, while those who place a greater value on avoiding treatment-related toxicity may decline.

Where available, a trial of a commercially-available oral cannabinoid (eg, dronabinol in the United States; nabilone where available) is reasonable. The use of smoked or vaporized cannabis (marijuana) or cannabidiol (CBD) oil for refractory cancer pain cannot be recommended. (See 'Cannabis and cannabinoids' above.)

-A trial of tizanidine, an alpha-2 adrenergic agonist, should be limited to patients who are not hemodynamically unstable, predisposed to serious hypotension, or encephalopathic from other causes. (See 'Alpha-2 adrenergic agonists' above.)

Neuropathic pain

Patients with depressed mood – If neuropathic pain is associated with a significantly depressed mood, we suggest first-line therapy with an antidepressant rather than a different type of adjuvant analgesic (Grade 2C). For most patients we prefer an SNRI such as duloxetine. (See 'Analgesic antidepressants' above.)

Others – For most patients with neuropathic pain that is unrelated to prior chemotherapy and not associated with a depressed mood, we suggest first-line therapy with gabapentin or pregabalin rather than an antidepressant (Grade 2C). We generally prefer pregabalin because dose adjustments are simpler. (See 'Gabapentin and pregabalin' above.)

For patients with chemotherapy-induced peripheral neuropathy, duloxetine is a preferred first-line agent. Specific recommendations are provided elsewhere. (See "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)

Refractory cases – Patients who don't respond to the initial drug trial may be considered for trials of the alternative gabapentinoid or alternative analgesic antidepressants. Another approach is to choose the next drug from a different class (eg, trying a gabapentinoid if an antidepressant is not effective), but there is no evidence to support this practice. If an adjuvant analgesic provides meaningful, but insufficient analgesia, another drug may be added if the risks are acceptable (eg, adding low-dose desipramine to a gabapentinoid).

Other options include a trial of oxcarbazepine or lacosamide, an alpha-2 adrenergic agonist (eg, tizanidine), or possibly a cannabinoid. For patients with focal, peripherally generated pain, a trial of a transdermal lidocaine patch is another option. (See 'Alpha-2 adrenergic agonists' above and 'Cannabis and cannabinoids' above and 'Other anticonvulsants' above and 'Topical therapies' above.)

Bone pain

Patients with multifocal bone pain are usually managed with a nonsteroidal anti-inflammatory drug, unless they have a specific contraindication to use of these agents, and an opioid. Specific recommendations are provided separately. (See "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs", section on 'Indications and contraindications'.)

Osteoclast inhibitors are indicated, in conjunction with an opioid, in patients with symptomatic bone metastases from a variety of cancers. As adjuvant agents, there is evidence to support the analgesic potential of all osteoclast inhibitors, although benefit seems modest in most patients. (See 'Osteoclast inhibitors' above.)

Use of bone-targeted radiopharmaceuticals, such as radium-223, is typically reserved for the patient with multifocal bone pain that is refractory to other treatment; most of the available data are in advanced prostate cancer. (See 'Bone-targeted radiopharmaceuticals' above.)

Glucocorticoids may be useful in patients with opioid-refractory bone pain, especially in with the setting of advanced illness and limited prognosis, or a "pain crisis," severe and escalating pain that is not responding sufficiently to an opioid. (See 'Glucocorticoids' above.)

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Topic 2815 Version 101.0

References

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