Version July 2025
INTRODUCTION —
Chronic pain is one of the most common reasons that patients seek medical attention. Chronic pain results from combined biologic, psychologic, and social factors, and most often requires a multifactorial approach to management. In addition to nonpharmacologic therapies, many patients require medications to manage pain. This topic will discuss an approach to pharmacologic management based on the type of pain and an overview of drug choices. Graded treatment recommendations can be found in treatment topics for specific chronic pain conditions (eg, chronic back pain, postherpetic neuralgia, fibromyalgia).
The general approach to the management of chronic non-cancer pain and nonpharmacologic therapies for chronic pain are discussed separately. Evaluation of chronic pain and the use of opioids for chronic non-cancer pain are also discussed separately.
●(See "Approach to the management of chronic non-cancer pain in adults".)
●(See "Evaluation of chronic pain in adults".)
●(See "Use of opioids in the management of chronic pain in adults".)
GENERAL PRINCIPLES OF DRUG SELECTION
Selection of agents — The optimal choice of pharmacologic therapy depends on the type of chronic pain syndrome (eg, nociceptive, neuropathic, or nociplastic) (table 1). (See "Evaluation of chronic pain in adults", section on 'Pathophysiology of pain'.)
Distinguishing among these chronic pain diagnostic categories is important because drug treatments often differ (table 2 and algorithm 1). Types of chronic pain sometimes overlap.
The patient's medical status (eg, cardiovascular, hepatic, renal, and cognitive issues) may affect the choice of drug, due to the potential for drug side-effects, drug clearance, and drug-drug interactions. Consistent with a biopsychosocial model of care, multimodal therapy that includes alleviation of disturbed sleep or depressed or anxious mood can significantly increase response to other drug and interventional treatments [1]. Involving family and caregivers may improve prescription compliance, and knowledge about available social support (eg, assistance with transportation) may affect decisions about the frequency of follow-up visits for monitoring and adjustment of drug doses.
We reserve opioids for patients in whom other therapies are either ineffective or contraindicated and evaluate the risk of non-compliance and misuse. Opioids should be used at the lowest dose and for the shortest intervals possible and should be continued only if they measurably improve function and quality of life without serious adverse effects. (See 'Opioids' below.)
Pain pathways and the effects of drugs on those pathways are shown in a figure (figure 1). Mechanisms of analgesic drug classes are shown in a table (table 3).
Pharmacologic therapy for nociceptive pain
●Nonsteroidal anti-inflammatory drugs (NSAIDs) – NSAIDs are the mainstay of treatment of musculoskeletal pain if pharmacologic therapy is required as part of multimodal therapy. However, the efficacy of NSAIDs for chronic musculoskeletal pain without evidence of ongoing inflammation is low (eg, chronic low back pain) [2]. Whenever possible, structural, inflammatory, or disease-related causes for pain should be targeted, which may reduce or eliminate the need for analgesics. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Start with nonpharmacologic therapy'.)
If NSAIDs prove ineffective for patients who are presumed to have nociceptive pain, the diagnosis of neuropathic pain or nociplastic pain or a combination could be considered, and a pain-relieving antidepressant (eg, duloxetine) or possibly antiseizure medication could be considered as an alternative. (See 'Pharmacologic therapy for neuropathic or nociplastic pain' below and "Approach to the management of chronic non-cancer pain in adults", section on 'Creating a plan for treatment'.)
●Antidepressants – The evidence of efficacy of antidepressants for relieving musculoskeletal pain is mixed, and any effect is likely small, though the majority of studies measured only short-term outcomes and excluded people with low mood and other mental health conditions. [3-5]. Efficacy has been most consistently demonstrated for duloxetine. (See 'Serotonin-norepinephrine reuptake inhibitors' below.)
●Acetaminophen – Acetaminophen is not considered a first-line therapy for chronic osteoarthritis or back pain due to lack of efficacy and concerns for hepatotoxicity when used at a higher than recommended dose. (See 'Acetaminophen' below.)
●Opioids – We avoid using opioids long-term whenever possible in patients with nociceptive pain. We consider using opioids only when the benefits outweigh the potential risks and when other lower risk and potentially more effective pharmacologic and nonpharmacologic therapies have failed to provide adequate pain relief and have not improved or have worsened function. (See "Use of opioids in the management of chronic pain in adults".)
Pharmacologic therapy for neuropathic or nociplastic pain
●First line therapy – For most patients with chronic neuropathic or nociplastic pain, initial treatment includes either select antidepressants (ie, tricyclic antidepressants [TCAs] or serotonin-norepinephrine reuptake inhibitors [SNRIs]) or antiseizure medications (ie, gabapentin or pregabalin) with adjunctive topical therapy (eg, topical lidocaine or capsaicin) when pain is localized (table 4) [6-10]. The effects of systemic medications on receptors and neurotransmitters involved with pain are shown in a table (table 5).
The choice among treatments should be individualized based on the pain condition (if known), patient-specific characteristics, co-occurring conditions, medication side effect profile, cost, and patient values and preferences. In practice, comorbidities and concurrent medications often favor one drug class or another (eg, start with an antidepressant if the patient is also depressed or anxious or a gabapentinoid when antidepressant drug-interactions or side-effects are problematic) (table 6). The narrower choice within a class is also influenced by the patient's age, preferences with regard to dosing frequency, side effects, and cost/formulary considerations.
●Combination therapy – Combination therapy with two agents from different classes is common, as appropriate use of first-line medications for neuropathic or nociplastic pain may lead to only partial reduction in pain or dose-limiting side effects. However, the data are not robust enough to suggest specific combinations [11-14]. Caution is required when combining potentially sedating medications, with or without opioids, in patients with other risk factors for complications, including chronic lung disease [15], cognitive impairment, and older age. A diagnosis of nociplastic pain especially lends itself to concurrent multidisciplinary approaches to the management of pain [16].
●Opioids – The efficacy of opioids for neuropathic pain is uncertain (table 4) [10,17]. Opioids should be considered a second- or third-line option for neuropathic or nociplastic pain, especially when there is an expectation that they may be prescribed long-term [17,18]. Opioids may be considered earlier in the treatment of select patients, such as those with high severity intractable pain, episodic exacerbations of severe pain, or neuropathic cancer pain [9]. Opioids may worsen nociplastic pain.
●Inadequate response to therapy – When pharmacologic treatments have not succeeded or as an adjunct to further improve response to prescribed drug therapies, we strongly recommend to our patients that non-pharmacologic treatments be introduced. This is especially important for nociplastic pain. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Nonpharmacologic therapies'.)
Choices of pharmacologic agents for specific neuropathic and nociplastic conditions are discussed separately in multiple topic reviews.
●(See "Postherpetic neuralgia", section on 'Management'.)
●(See "Management of diabetic neuropathy", section on 'Pain management'.)
●(See "Trigeminal neuralgia", section on 'Treatment'.)
●(See "Fibromyalgia: Treatment in adults", section on 'Initial pharmacologic therapy'.)
●(See "HIV-associated distal symmetric polyneuropathy (HIV-DSPN)", section on 'Management of symptoms'.)
NONOPIOID ANALGESICS —
Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, norepinephrine re-uptake inhibiting antidepressants, and antiseizure agents are the most commonly used nonopioid analgesics (table 7).
Nonsteroidal anti-inflammatory drugs — NSAIDs are a mainstay of treatment of acute pain and can be used for chronic pain as well.
●Uses and efficacy – Both the nonselective NSAIDs and the more selective cyclooxygenase-2 (COX-2) inhibitors are primarily indicated for mild to moderate pain, particularly musculoskeletal pain, although a number of newer compounds carry an indication for severe pain. NSAIDs may be useful for chronic pain that persists due to underlying inflammation (eg, arthritis). In addition, NSAIDs are among the most commonly used and effective drugs for the treatment of chronic cancer pain [19].
For patients with musculoskeletal pain with multiple joints involved and without contraindications to NSAIDs, oral NSAIDs are appropriate first-line medications. Topical NSAIDs may be used for patients with localized arthritis of superficial joints (eg, hand and wrist, foot and ankle, or knee), with the potential to achieve therapeutic synovial tissue drug levels with lower systemic drug levels compared with oral therapy. (See "Overview of the management of osteoarthritis", section on 'Pharmacologic therapy'.)
Topical agents may also be appropriate for focal myofascial pain conditions. (See 'Topical agents' below.)
Usual doses, selected characteristics, and therapeutic roles of NSAIDs are shown in a table (table 7).
NSAIDs are synergistic with opioids, producing a modest dose-sparing effect.
Therapeutic uses for NSAIDs, including selective COX-2 inhibitors, and adverse effects are discussed separately. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Overview of COX-2 selective NSAIDs" and "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs: Adverse cardiovascular effects".)
●Mechanism of action – The primary effect of NSAIDs is to inhibit cyclooxygenase (COX). COX catalyzes arachidonic acid metabolism yielding prostanoids, which play a significant role in inflammation and certain pain conditions. The analgesic effect of NSAIDs derives both from its peripheral action on the COX enzyme as well as an effect on the central nervous system, at least in certain pain states [20]. Inflammation sensitizes peripheral nociceptors, which may create a hyper-nociceptive milieu and thereby increase ascending nociceptive signaling [21]. (See "NSAIDs (including aspirin): Pharmacology and mechanism of action" and "NSAIDs: Therapeutic use and variability of response in adults" and "Overview of COX-2 selective NSAIDs".)
●Toxicity – There is individual variation in therapeutic and adverse responses to NSAIDs. NSAIDs are associated with gastropathy, renal toxicity, platelet inhibition, and cardiovascular risk, in addition to drug-drug interactions. (See "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs: Adverse cardiovascular effects".)
For patients who chronically take NSAIDs, treatment trials on and off the NSAIDs should be considered to avoid unnecessary polypharmacy and attendant risks.
For specific drug interactions, use the drug interactions program included with UpToDate.
Acetaminophen — Acetaminophen is very commonly used for acute pain, particularly in combination with an NSAID, and is often considered for chronic pain.
●Uses and efficacy – Though commonly used, evidence of acetaminophen's efficacy for chronic pain is limited, with at best a subset of patients receiving sustained meaningful analgesia [21-23]. It is reasonable to consider acetaminophen as an adjunct for mild to moderate musculoskeletal pain or episodes of acute or chronic pain in patients who report benefit.
The combination of acetaminophen with an NSAID has not been evaluated for chronic pain, though this combination is commonly used for acute pain. (See "Nonopioid pharmacotherapy for acute pain in adults", section on 'Strategy for multimodal nonopioid pharmacotherapy'.)
●Mechanism of action – The analgesic mechanism of acetaminophen is uncertain [22]. Acetaminophen does not have meaningful peripheral anti-inflammatory effects but is sometimes categorized as an NSAID since evidence suggests a predominantly central nervous system effect on prostaglandin synthesis [23].
●Dosing and toxicity – There is controversy over the maximum safe daily dose of acetaminophen, primarily related to liver toxicity. The US Food and Drug Administration (FDA) recommended maximum dose of acetaminophen is 4000 mg per day [24]. However, for long-term use many experts and manufacturers limit the daily dose to 3000 mg orally in adults with normal liver function, particularly when used for longer durations (eg, >7 days) or 2000 mg per day for older patients and for patients with liver disease. (See "Acetaminophen (paracetamol): Drug information" and "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation".)
When prescribing opioids, we avoid combination preparations that contain acetaminophen (eg, hydrocodone, oxycodone, tramadol, or codeine with acetaminophen) to allow appropriate dosing of each component and to avoid toxicity of the nonopioid drug. When calculating the total daily dose of acetaminophen, it is important to inquire about all sources of acetaminophen, including prescription and over the counter medications. Many patients are unaware that several over-the-counter products contain acetaminophen (eg, cough and cold combination products), making it easy to accidentally ingest too high of a dose of acetaminophen.
Other risk factors for hepatotoxicity include older age, poor nutritional status, fasting/anorexia, and concurrent use of other drugs that interact with acetaminophen metabolism (eg, St. John’s wort, phenobarbital) [25,26].
In addition to hepatotoxicity, chronic acetaminophen use may be associated with chronic kidney disease, hypertension, chronic daily headache, and peptic ulcer disease. (See "Epidemiology and pathogenesis of analgesic-related chronic kidney disease", section on 'Acetaminophen' and "NSAIDs and acetaminophen: Effects on blood pressure and hypertension", section on 'Effects of acetaminophen on blood pressure' and "Unusual causes of peptic ulcer disease", section on 'Non-NSAID medications'.)
ANTIDEPRESSANTS —
Some specific categories of antidepressants are among the first-line treatments for many neuropathic pain disorders. Antidepressants are a heterogeneous group of medications approved to treat major depressive disorders. Both tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) possess analgesic qualities.
●Comparative efficacy – Multiple studies have found that TCAs and SNRIs may provide effective pain relief in neuropathic pain conditions with a number needed to treat of 3.6 to 6.4, respectively, for one patient to achieve at least 50 percent pain relief [6]. TCAs and SNRIs may be effective for a wide range of pain conditions, including neuropathic pain (eg, diabetic neuropathic pain, postherpetic neuralgia, and spinal radicular pain) and nociplastic pain (eg, fibromyalgia and irritable bowel syndrome), and appear less effective for nociceptive pain such as low-back pain [27-32].
The evidence for analgesic effects is strongest for SNRIs, and antidepressants with the greatest effect upon norepinephrine seem to have the greatest analgesic effect [27,28]. The analgesic response from norepinephrine re-uptake inhibition results from subsequent up-regulation of the descending inhibitory pain pathways [33,34].
In a 2023 network meta‐analysis of randomized trials that evaluated analgesic efficacy of 25 different antidepressants for various types of chronic pain, moderate to high certainty evidence of efficacy was found only for duloxetine (an SNRI) [3]. Milnacipran resulted in a small reduction in pain intensity, though the certainty of evidence was lower than for duloxetine.
The evidence for the efficacy of highly selective serotonin reuptake inhibitors (SSRIs) is minimal and completely lacking for musculoskeletal pain [35,36]. SSRIs can address co-occurring anxiety and depression that are often associated with chronic pain. However, when they are used in combination with TCAs and SNRIs they can complicate polypharmacy and risk adverse effects. We routinely coordinate with other providers who are currently or considering prescribing SSRIs when recommending addition of TCAs or SNRIs. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects" and "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects" and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects".)
TCAs or SNRIs are indicated for treatment of neuropathic and nociplastic pain even in the absence of mood disturbance. Analgesic antidepressants provide pain relief separate from their antidepressant effects, with analgesic effects known to occur in non-depressed patients. We emphasize to our patients, families and caregivers that antidepressants are not just for depression, and the mechanism of action for neuropathic analgesia is likely different than the mechanism of action for depression. This approach may encourage patient acceptance and compliance, especially for those who are reluctant to take antidepressants. For some patients, managing cooccurring depression and anxiety may also contribute to relief of pain. (See "Evaluation of chronic pain in adults", section on 'Psychiatric comorbidity'.)
The role of antidepressants in the management of fibromyalgia and chronic low back pain is discussed separately. (See "Fibromyalgia: Treatment in adults", section on 'Initial pharmacologic therapy' and "Subacute and chronic low back pain: Management".)
●Administration – Noticeable analgesic (and antidepressant) effects may require two to four weeks of antidepressant therapy, possibly due to the time necessary to increase production of neuroprotective proteins, such as brain-derived neurotrophic factor [37]. In the authors' experience, many purported treatment failures are a result of too low a dose and/or too short a duration for a clinically meaningful improvement to occur. Doses of antidepressants used for chronic pain and agent specific common side effects are shown in tables (table 4 and table 8).
Tapering and discontinuing antidepressants can be challenging. Abruptly stopping or rapidly tapering can cause agitation, anxiety, chills, diaphoresis, dizziness, dysphoria, fatigue, headache, insomnia, irritability, myalgias, nausea, paresthesias, rhinorrhea, and tremor. Discontinuing antidepressants is discussed in detail separately. (See "Discontinuing antidepressant medications in adults".)
Tricyclic antidepressants — TCAs remain an appropriate treatment for a variety of chronic pain conditions with or without coexisting depression, despite the fact that none of the TCAs carry a US Food and Drug Administration (FDA) labeled primary indication for pain management [38,39]. They are preferred therapy for most patients with neuropathic-predominant postherpetic neuralgia. (See "Postherpetic neuralgia", section on 'Neuropathic-predominant pain'.)
The authors continue to recommend TCAs as a frequently less costly and demonstrably effective treatment for neuropathic and nociplastic pain based upon long-term clinical experience and careful consideration of risks. Since depression and anxiety are highly co-prevalent in chronic pain conditions (and are the leading causes of suicide and disability worldwide), TCAs continue to be beneficial in both depressed and non-depressed patients. In addition to analgesia, TCAs may improve co-occurring sleep and mood disorders, which are prevalent and often left untreated in patients with chronic pain. However, because of potential risks of cardiac arrhythmias at higher doses, many clinicians have chosen to avoid prescribing TCAs, particularly in patients taking antiarrhythmics and in older patients [4,40-42].
Most older studies supporting TCAs for pain are small, measured only short-term outcomes, and excluded patients with mood disorders, unlike more recent studies of other newer antidepressants, such as SNRIs [3]. However, in one randomized trial of patients with painful diabetic neuropathy, amitriptyline provided effective analgesia to a similar extent in patients with and without depression [43].
●Types of TCAs – TCAs can be divided into tertiary amines and their demethylated secondary amine derivatives. In addition, maprotiline (Ludiomil) is often considered in this drug class, although it is a tetracyclic antidepressant. Amitriptyline has been the most widely studied TCA in chronic pain [44,45]. A number of others, including doxepin, imipramine, nortriptyline, and desipramine also have been used effectively. Amitriptyline is the only TCA with proven efficacy for prevention of migraine, though others are widely used. (See "Preventive treatment of episodic migraine in adults", section on 'Antidepressants'.)
TCAs have antihistaminic side effects that may be desirable in patients who have problems with sleep initiation and maintenance. Anticholinergic effects, which do not appear to contribute to analgesia, are common and may lead to dose limitation and discontinuation.
●Pretreatment evaluation – TCAs have been associated with heart block, ventricular arrhythmias, and sudden death. Before initiating treatment with any of the cyclic antidepressants, patients should be considered for screening for cardiac conduction system disease, which may preclude the use of these medications [4,40-42]. Pretreatment evaluation and screening are discussed in detail separately and are shown in an algorithm (algorithm 2). (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Cardiac evaluation'.)
●Dosing – TCAs should be started at a low dose, with dosing slowly escalated as tolerated. As an example, nortriptyline may be started at 10 mg/day orally, increasing the dose at weekly intervals in 10 to 25 mg increments based on response and tolerability to a dose of 75 to 150 mg daily at bedtime. It can take up to 6 to 12 weeks, including two weeks at the highest dose tolerated, for an adequate trial of treatment with TCA. Effective analgesia has been reported at lower doses than those required for treatment of depression [9,46], there is no strong evidence to support this low dose approach. The authors do prescribe at higher antidepressant doses when therapeutic benefits are unmet at lower doses and side effects are not dose limiting (table 8). The authors have found that many purported treatment failures are a result of too low a dose and/or too short a duration for a clinically meaningful improvement to occur (table 4).
For older patients, the starting doses of tricyclics should be reduced by one-half and the doses escalated slowly while watching carefully for side effects. Note that the American Geriatrics Society Beers criteria for potentially inappropriate medication use in older adults includes TCAs [47]. (See "Treatment of chronic non-cancer pain in older adults", section on 'Antidepressants'.)
Absorption and clearance of TCAs may vary. We commonly check blood levels for patients who are taking ≥150 mg daily, particularly for patients who are also taking anti-arrhythmic drugs. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Plasma levels and therapeutic response'.)
●Side effects and choice of drug – TCAs are associated with multiple undesirable adverse effects that vary depending on the individual agent (table 8). Adverse effects are dose-related and include anticholinergic effects, antihistaminic effects, alpha-1 adrenergic receptor blockade, and cardiac effects (ie, increasing intraventricular conduction, prolonged QT interval, prolonged conduction through the atrioventricular node). TCAs are relatively contraindicated in patients with severe cardiac disease, particularly conduction disturbances. (See "Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects", section on 'Side effects'.)
Nortriptyline is our preferred initial TCA since it is less sedating and with fewer anticholinergic side effects than amitriptyline. Among the TCAs, amitriptyline is among the most sedating and most potent anticholinergic effects. Thus, we rarely prescribe amitriptyline as the first choice TCA for chronic pain, unless sleep initiation and maintenance is a problematic complaint. Anticholinergic adverse effects including dry mouth, orthostatic hypotension, constipation, and urinary retention can be reduced by starting with low doses administered at bedtime and with slow titration to higher doses (table 8).
Use of TCAs for specific chronic pain conditions is discussed separately. (See "Management of diabetic neuropathy", section on 'Tricyclic drugs' and "Complex regional pain syndrome in adults: Treatment, prognosis, and prevention", section on 'Adjuvant medications for neuropathic pain' and "Postherpetic neuralgia", section on 'Tricyclic antidepressants'.)
Serotonin-norepinephrine reuptake inhibitors — Among the SNRIs, venlafaxine and duloxetine have been used for treatment of peripheral neuropathic pain, and duloxetine and milnacipran have been used for treatment of fibromyalgia. A 2023 network meta-analysis of randomized trials that evaluated efficacy of the most commonly used antidepressants across a broad range of chronic pain conditions found that duloxetine, the most extensively studied antidepressant drug, was modestly effective for improving function, sleep, and quality of life for patients, with moderate to high certainty of the evidence [48]. Milnacipran, a more potent inhibitor of norepinephrine reuptake than the other SNRIs, was also modestly effective for pain relief, with fewer available studies and lower certainty of the evidence. For both duloxetine and milnacipran, standard doses were found to be as efficacious as high doses, though we have observed that on occasion higher doses may be useful when patients are carefully monitored for benefits and side effects. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects".)
Duloxetine — Of all antidepressants, duloxetine has the largest evidence base to support analgesic efficacy for the treatment of painful diabetic neuropathy, fibromyalgia, and chronic musculoskeletal pain [3,49-51]. In addition to these pain indications, duloxetine is used to treat major depression, anxiety, and stress urinary incontinence.
The most common side effects include nausea, dry mouth, insomnia, drowsiness, constipation, fatigue, and dizziness (table 8). Side effects are reduced by administering duloxetine 30 mg orally once daily for one week before increasing to the usual dose of 60 mg once daily. The authors will occasionally increase the dose as high as 120 mg daily in order to maximize analgesia from the increased norepinephrine reuptake inhibition that occurs at higher doses, with attention to the potential for serotonin side effects. In patients sensitive to side effects, we often start at 20 mg and adjust the dose upwards based on patient response.
Duloxetine should be avoided in patients with hepatic or severe kidney dysfunction. Gradual tapering is recommended at discontinuation to avoid withdrawal symptoms. (See "Discontinuing antidepressant medications in adults", section on 'SNRIs'.)
Doses and efficacy of duloxetine for painful diabetic neuropathy, chronic back pain, and fibromyalgia are discussed separately.
●(See "Management of diabetic neuropathy", section on 'Duloxetine'.)
●(See "Management of moderate to severe knee osteoarthritis", section on 'Duloxetine'.)
●(See "Fibromyalgia: Treatment in adults", section on 'Patients with severe fatigue and/or depression'.)
●(See "Subacute and chronic low back pain: Management", section on 'Duloxetine'.)
Milnacipran — Milnacipran is a newer SNRI that inhibits norepinephrine reuptake more so than serotonin inhibition, and hence may be more potent for the management of both neuropathic and nociplastic pain conditions. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Milnacipran'.)
Venlafaxine — Venlafaxine may be used to treat acute and chronic neuropathic pain [52]. At low doses venlafaxine has activity similar to an SSRI, but its norepinephrine reuptake properties prevail as the dose is increased (table 4).
Venlafaxine should be prescribed with caution in patients with cardiac disease, as cardiac conduction abnormalities have been reported in a small number of patients, and blood pressure increases can occur (table 8). Discontinuation symptoms are particularly likely when venlafaxine is stopped, due to its short half-life. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects", section on 'Discontinuation'.)
The use of venlafaxine for treatment of diabetic neuropathy is discussed separately. (See "Management of diabetic neuropathy", section on 'Venlafaxine'.)
ANTISEIZURE MEDICATIONS —
Gabapentinoids (ie, gabapentin and pregabalin) are the antiseizure medications that are among the first line therapies for neuropathic pain (table 4) [53].
Gabapentin and pregabalin — The gabapentinoids have proven efficacy versus placebo in several neuropathic pain conditions [9,54-56]. Gabapentin has primarily been studied and found effective for the treatment of postherpetic neuralgia and painful diabetic neuropathy; evidence for efficacy in other types of neuropathic pain is limited [57,58]. A 2019 systematic review of 45 randomized trials of pregabalin in patients with postherpetic neuralgia, painful diabetic neuropathy, or mixed neuropathic pain found pregabalin at doses of 300 to 600 mg daily more effective than placebo [59]. Response rates were lower for patients with central neuropathic pain or fibromyalgia, compared with patients with postherpetic neuralgia or painful diabetic neuropathy. There was no evidence of efficacy for patients with HIV neuropathy. (See "Chronic complications of spinal cord injury and disease", section on 'Pain syndromes'.)
For patients with neuropathic pain that is incompletely controlled with opioids, the addition of a gabapentinoid may be beneficial. However, this combination requires close follow-up and assessment of benefits versus risks of sedation, respiratory depression, and overdose due to drug-drug interaction, as discussed below.
Gabapentin and pregabalin bind to the voltage-gated calcium channels at the alpha 2-delta subunit in the central nervous system. While the binding sites are well characterized, the mechanisms leading to pain relief are likely diverse [60,61].
●Gabapentin dosing – Treatment with gabapentin should be initiated at a low dose with gradual increases until pain relief is achieved or dose-limiting adverse effects occur. Gabapentin is typically initiated at 300 mg at night. In patients with sensitivities, vulnerability to nocebo effects, and elderly patients consider a starting dose of 100 mg at night to minimize initial side effects.
The typical effective daily dose range for immediate-release (IR) gabapentin is 1200 to 2400 mg/day divided into three doses, with a maximum daily dose of 3600 mg. As gabapentin can be sedating, the authors at times dose it asymmetrically with a larger dose at night to facilitate sleep. For the extended-release (ER) formulation, one regimen starts with 300 mg orally once daily, gradually increasing to a maximum of 1800 mg orally once daily if needed. Adjustment for renal impairment is required for both IR and ER, and use of ER is not recommended in patients with severe kidney dysfunction.
Gabapentin may not be reliably absorbed due to an active L-amino transport system in the proximal small bowel that is both saturable and dose-dependent. An adequate trial of treatment with gabapentin can require two months or more [57].
●Pregabalin dosing – We typically start pregabalin (IR) with a nighttime dose only, and increase the dose as tolerated on a twice daily dosing schedule. In most patients we start with 50 or 75 mg and work up to the effective range of 150 to 450 mg a day based on tolerability and effect. We may start with a lower dose in elderly or sensitive patients and titrate more slowly. Further titration (maximum dose 600 mg daily) after two to four weeks may be considered if necessary. As with gabapentin, the authors at times dose it asymmetrically with a larger dose at night to facilitate sleep. Adjustment for kidney dysfunction is required for both immediate and ER, and use of ER is not recommended in patients with severe kidney dysfunction. Older patients should be started at half dosages, or less to minimize risks of falling and sedation.
Pregabalin may provide analgesia more quickly than gabapentin, both because a lower initial dose may be efficacious and because a shorter time is required to titrate to a full dose [62]. Pregabalin is well absorbed with high oral bioavailability.
●Adverse effects – Adverse effects of antiseizure medications are discussed in detail separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Antiseizure medications'.)
Gabapentin and pregabalin can produce dose-dependent dizziness and sedation that can be reduced by starting with lower doses and titrating slowly.
Gabapentinoids may be associated with increased risks of depression and suicide, unintentional overdose, and motor vehicle accidents [63,64]. Other important side effects or complications include the following:
•Respiratory depression – Respiratory depression has been reported in older patients and in those who receive gabapentin along with other analgesics and sedatives [65,66]. Coprescription of gabapentinoids with opioids has been associated with an increased risk of opioid-related overdose and caution is advised when combining these classes of medication [67-69]. In a population-based cohort study of patients with known chronic obstructive lung disease (COPD), gabapentinoid prescribed for epilepsy, neuropathic pain and other chronic pain conditions was associated with increased risk for severe exacerbation and respiratory failure [15]. A two-fold increase in risk was found regardless of age, sex, and various markers of COPD severity.
•Misuse – Caution is also advised when prescribing these drugs to incarcerated patients and individuals with substance use disorders, as this class of medications has misuse potential due to their psychoactive effects, especially at higher doses [70,71]. Misuse of gabapentinoids, in particular pregabalin, has become increasingly recognized, with evidence suggesting that these drugs may be primary agents of misuse [72]. Pregabalin has always been a Schedule V controlled substance per the United States Drug Enforcement Agency. Gabapentin has been made a Schedule V controlled substance in some states, and a number of states have mandated reporting of gabapentin in their Prescription Drug Monitoring Programs [73]. Gabapentin is a controlled drug in the United Kingdom [74]. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Gabapentin' and "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Pregabalin'.)
•Opioid overdose – Gabapentinoids may be associated with an increased risk of overdose and death [67-69]. In a population-based study of approximately 6500 patients who were receiving prescription opioids, concomitant use of pregabalin was associated with a dose-related increase in the risk of opioid related mortality (odds ratio [OR] 1.52 [95% CI 10.4-2.2] for low dose pregabalin, OR 2.0 [95% CI 1.24-5.06] for high dose pregabalin) [75]. In a Centers for Disease Control (CDC) analysis of 2019 to 2020 data from the State Unintentional Drug Overdose Reporting System (SUDORS) in 23 states and the District of Columbia, gabapentin was detected in nearly 90 percent of fatal opioid overdoses [76].
We agree with the recommendations that providers should be aware of the risk of gabapentin misuse in patients with current or a history of opioid use disorder [77-79]. When gabapentinoids are prescribed there should be clear plans for the duration of a trial, measures to determine if beneficial, parameters for stopping treatment, and patients should be monitored for misuse (see "Prescription drug misuse: Epidemiology, prevention, identification, and management"), and urine drug testing. (See "Urine drug testing for patients with chronic pain".)
Other antiseizure medications — Data informing the use of carbamazepine and oxcarbazepine for neuropathic pain are limited. Carbamazepine or oxcarbazepine are the initial therapies for trigeminal neuralgia. Carbamazepine is best studied for this indication. (See "Trigeminal neuralgia", section on 'Treatment'.)
Limited evidence from short-term trials suggests carbamazepine is probably effective for other chronic neuropathic pain [80], but its use may be limited by side effects. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.)
Other antiseizure medications, including topiramate, lamotrigine, levetiracetam, phenytoin, sodium valproate, zonisamide, tiagabine, and the benzodiazepine clonazepam, have been utilized anecdotally and in randomized trials for various pain conditions [81]. Evidence of their effectiveness is limited, and in general, these agents should be reserved for specialty care, as third-line treatment in patients who have not responded to or cannot tolerate other medications. A 2013 systematic review of lamotrigine for acute and chronic pain concluded that it does not have a place in the treatment of pain, given other more effective therapies [82]. A 2014 systematic review of studies of levetiracetam found no evidence to support its use for neuropathic pain [83], consistent with a strong recommendation against use in a 2015 review of pharmacotherapy for neuropathic pain [6].
Laboratory monitoring for patients who receive antiseizure medications is discussed separately. (See "Antiseizure medication maintenance therapy and drug monitoring", section on 'ASM levels'.)
OTHER ADJUVANT MEDICATIONS —
When usual medication regimens are not effective, a degree of exploration and innovation may be required, including the administration of other adjuvant medications to potentiate analgesia. To minimize polypharmacy, on-off-on trials may help determine if medications are beneficial; they should be discontinued if improvement does not occur.
Other than laxatives, we rarely add drugs to treat side-effects associated with analgesics, and certainly do not recommend the addition of stimulants to overcome sedation.
Topical agents — Topically applied drugs have several potential advantages over systemic drugs for pain, including delivery at the painful site of injury and significantly lower initial rates of systemic absorption so fewer systemic effects (table 9). However, significant systemic concentrations and systemic side effects are possible.
Topical agents may be offered as first-line therapy for very well-localized nociceptive or neuropathic pain conditions, though are more commonly prescribed as an adjunct to systemic medication.
●Topical nonsteroidal anti-inflammatory drugs (NSAIDs) – Topical NSAIDs, in the form of a gel, spray, or cream, can provide relief for acute musculoskeletal pain [84] and may be beneficial in patients with single joint osteoarthritis [85]. Evidence of effectiveness for these agents for other chronic pain conditions is lacking. The risk of gastrointestinal, renal, and cardiovascular toxicity is much lower with topical NSAIDs as compared with its oral formulation due to the reduced systemic absorption (5- to 17-fold lower for topical diclofenac compared with oral [86,87]). Topical NSAIDs may be better tolerated than oral preparations, with mild skin rashes being the most commonly reported side effect. (See "Management of knee osteoarthritis", section on 'Topical NSAIDs' and "Management of hand osteoarthritis", section on 'Topical NSAIDs'.)
●Topical lidocaine – Topical lidocaine is considered second-line therapy for some forms of neuropathic pain [6]. For chronic pain, topical lidocaine is usually used in the form of a patch or plaster. Data supporting the efficacy of topical lidocaine are limited [88], and the best evidence suggests that it may be beneficial for postherpetic neuralgia, and possibly for painful diabetic neuropathy. (See "Management of diabetic neuropathy", section on 'Topical therapies or neuromodulation' and "Postherpetic neuralgia", section on 'Adjunctive topical and nonpharmacologic options'.)
Each 5% lidocaine patch contains 700 mg of lidocaine. Up to three patches may be applied simultaneously within a 24-hour period, but only for a maximum of 12 hours, followed by a patch-free interval of at least 12 hours. Systemic absorption of lidocaine when used according to this regimen is low (approximately three percent) [89], but topical lidocaine should be used cautiously in patients with hepatic, renal, or cardiac dysfunction.
●Topical capsaicin – Capsaicin has been used in patients with postherpetic neuralgia, human immunodeficiency virus(HIV) neuropathy, diabetic neuropathy, and in patients with osteoarthritis in one or a few joints.
•(See "Postherpetic neuralgia", section on 'Adjunctive topical and nonpharmacologic options'.)
•(See "Management of diabetic neuropathy", section on 'Topical therapies or neuromodulation'.)
•(See "Management of knee osteoarthritis", section on 'Topical capsaicin'.)
Capsaicin is an agonist of transient receptor potential vanilloid member 1 (TRPV1), a receptor prominent in small nerve fibers (a delta and c fibers) involved in pain [90,91]. Analgesia likely results from short-term desensitization and long term defunctionalization of nociceptor terminals with a dose-dependent impact [92]. It is available over-the-counter as low concentration (up to 0.1%) cream, lotion, or gel. Low concentration capsaicin preparations must be applied three to four times per day over the entire painful area for up to six to eight weeks before optimal pain relief can be achieved.
High concentration patches (8%) are also available by prescription and administered by a health care professional. The 8 % patch usually requires pretreatment with topical or injected lidocaine and often other stronger oral or intravenous (IV) analgesics during the treatment, to reduce local pain. Treatment application (30 minutes for diabetic neuropathic pain and 60 minutes for post-herpetic neuropathic pain) can be repeated every three months, with evidence suggesting a progressive response with repeated application [93]. The major adverse effects of capsaicin are burning, stinging, and erythema at the site of application, leading to intolerance in up to one-third of patients.
Cannabis and cannabinoids — The use of cannabis and cannabinoids for chronic pain is controversial and is complicated by the mixed and varied legal status (ie, recreational and medical) of these substances across the United States. Cannabis contains multiple pharmacologically active compounds. The best studied are the psychoactive constituent delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD); it is likely that any analgesic effects come from THC rather than CBD [94]. Available preparations are discussed separately. (See "Medical use of cannabis and cannabinoids in adults".)
The authors practice in a state where recreational and medicinal cannabis use is legal. With increasing legalization across the United States, it is likely that patients with chronic pain will seek approval or a specific recommendation for the use of cannabis or CBD [95].
Use of cannabis or cannabinoids for pain — In areas where cannabis use is legal we occasionally suggest a trial of cannabis or cannabinoids to patients who are at low risk for misuse, who have tried other approaches for pain management, and who have realistic expectations, given unclear evidence of benefit. Considerations with respect to cannabis include the following:
●We recommend against cannabis in patients with cannabis use disorder or prior or current substance use disorder.
●Importantly, we recommend discontinuation of cannabis that has been used as an analgesic but has not reduced pain or improved function and quality of life.
●We warn patients about the impact of cannabis on safe automobile and other equipment operation, especially in combination with alcohol.
●We do not routinely discontinue prescription of other prescribed analgesic drugs, including opioids, when the patient reports medicinal or recreational cannabis use, as long as the patient is an active participant in all other recommended aspects of multimodal pain management.
●We no longer routinely monitor urine for the presence of cannabis, since it is present in urine for weeks (when used episodically) or months (when used daily) after use.
Efficacy — A 2021 international guideline gave only a weak recommendation in support of the use of cannabis and cannabinoids for chronic pain due to the close balance between benefits and harm of therapy [96]. Systematic reviews and meta-analyses of trials including multiple patient populations and formulations of cannabis and cannabinoids have reported mixed results on efficacy for chronic pain [94,96-108].
Examples include the following:
●Cannabis – In a 2018 meta-analysis of 47 randomized trials of cannabis use for various types of chronic pain, there was moderate evidence that cannabis reduced pain by 30 percent, however, adverse event rates were high [97]. Based on pooled event rates, the number needed to treat for benefit was 24 (95% CI 15-61) and the number needed to harm was 6 (95% CI 5-8). In most studies, cannabis was used as an adjunct to other pain therapies.
●Cannabinoids – A 2022 Agency for Health Research and Quality systematic review of various THC-CBD doses and concentrations of synthetic and plant-extracted cannabis products found small, short-term improvements in neuropathic chronic pain and function [105]. Higher doses were associated with increased risk of dizziness, sedation, and nausea. Conclusions from this review are limited by non-standardized characterization of various cannabis products and lack of adequate studies on specific preparations and patient populations.
Adverse effects — Short-term adverse effects of cannabis and cannabinoids include dizziness, dry mouth, nausea, vomiting, fatigue, drowsiness, euphoria, confusion, hallucination, and loss of balance [98,107]. Due to increasing potency and variable routes of self-administration, there is potential for increased risk of side-effects associated with on-line and commercial cannabinoid products from dispensaries [109]. There are concerns about rising incidence of cannabis use disorder [110], calling for increased awareness among clinicians and education for patients. (See "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects", section on 'Risk factors for cannabis use and disorder'.)
The long-term adverse effects of medical cannabis use are not known. One prospective cohort study followed 431 patients with chronic pain for one year and compared patients using medical cannabis with nonusers [111]. There was no difference in serious adverse events between the two groups. However, the medical cannabis group had a higher rate of non-serious respiratory adverse events. (See "Cannabis use and disorder: Epidemiology, pharmacology, comorbidities, and adverse effects".)
Botulinum toxin — Intradermal botulinum toxin injections may be beneficial for some patients with neuropathic pain. However, existing trials are small and heterogeneous, and optimal dosing regimens have not been established.
A systematic review of the literature found 14 randomized placebo controlled trials of the use of botulinum for various types of neuropathic pain. Botulinum toxin injection reduced pain scores, though whether this was a clinically relevant difference was unclear [112]. In one trial including patients with postherpetic neuralgia, botulinum toxin injection reduced pain scores and the percent of patients using opioids for three months after injection [113].
Use of botulinum toxin for postherpetic neuralgia is discussed separately. (See "Postherpetic neuralgia", section on 'Intradermal onabotulinumtoxinA injections'.)
Adjuvants we do not recommend
Muscle relaxants — We avoid ongoing use of the drugs referred to as muscle relaxants (eg, methocarbamol, metaxalone, carisoprodol) for patients with chronic pain. A wide variety of pain conditions may be accompanied by painful muscles, and at times spasm. However, there is no evidence that these medications directly relax muscles. Muscle relaxants have diverse pharmacologic actions, but none of them act directly on muscle itself [114]. Pain relief and relief of spasm without spasticity may be related to central nervous system effects, including sedation, rather than analgesic effects. When true muscular spasticity is present, anti-spasticity drugs, such as baclofen or tizanidine, may alleviate the pain from persistent tonic muscular contractions. (See "Chronic complications of spinal cord injury and disease", section on 'Spasticity'.)
Carisoprodol should no longer be used for any indication, due to lack of proven efficacy, high rates of physical dependence, and risk of agitation and delirium tremens when abruptly withdrawn.
Cyclobenzaprine is an alternative initial drug for patients with mild to moderate symptoms of fibromyalgia. It is a tricyclic closely resembling amitriptyline, with a presumed mechanism similar to other TCAs and unrelated to muscle relaxation. Doses and efficacy for patients with fibromyalgia are discussed separately. (See "Fibromyalgia: Treatment in adults", section on 'Cyclobenzaprine'.)
Tizanidine and cyclobenzaprine are best studied for acute low back pain, with minimal evidence of efficacy for chronic back pain [115,116]. Some UpToDate contributors prescribe these medications as a temporary measure (up to four weeks) for patients with subacute or chronic low back pain for whom NSAIDs are ineffective. (See "Subacute and chronic low back pain: Management", section on 'Skeletal muscle relaxants for short-term relief'.)
Muscle relaxants have anticholinergic properties, and may also cause central nervous system depression. They should be used cautiously in older patients, and when combined with other central nervous system depressant medications or antidepressants. When used along with tricyclic antidepressants (TCAs), muscle relaxants may increase TCA side effects of sedation, dry mouth, urinary retention, and possibly arrhythmias.
Benzodiazepines — We avoid the use of benzodiazepines in patients with chronic pain, including those with anxiety or post-traumatic stress disorder. Benzodiazepines are not first-line anxiolytics or sleep aids and there is no evidence of analgesic efficacy for chronic pain. Disadvantages include their misuse and addictive potential, and importantly, potentiation of respiratory depression and an increase in all-cause mortality with concomitant opioid use. (See "Use of opioids in the management of chronic pain in adults", section on 'Drug interactions'.)
In a study of 1220 patients with non-cancer pain taking long-term opioids, concurrent benzodiazepine use was associated with greater pain severity, prescription of higher doses of opioids, substance use, and greater co-occurring mental health problems [117].
OPIOIDS —
Based on compelling evidence of risk and absent strong evidence of effectiveness [118-121], long-term opioids should not routinely be used for chronic pain. If opioids are necessary, they should be used at the lowest effective dose, for the shortest duration possible, with ongoing reassessment of risks, benefits, and treatment adherence [122]. They should only be used when benefits outweigh the risks. Opioids should generally be used only when other therapies (nonpharmacologic therapy, nonopioid pharmacologic therapy, effective cancer treatment) have failed to provide adequate pain relief and improved function. They should be combined with nonpharmacologic and often nonopioid pharmacologic therapy. (See "Use of opioids in the management of chronic pain in adults", section on 'Indications for opioid therapy'.)
Chronic opioid therapy should be reserved for patients who are carefully assessed to be at low risk for substance use disorder, and should especially be avoided in patients with co-occurring conditions that increase the risk of opioid related respiratory depression (eg, sleep apnea or other chronic respiratory disorders). Severe or end-stage kidney disease adds significant risk to prescribing many common opioids due to poor clearance of metabolites or active drugs. This is less of an issue with methadone, fentanyl and buprenorphine (table 10) [123]. Hepatic insufficiency also reduces clearance and increases risk of encephalopathy, notably with methadone [124]. Concomitant use of opioids with other sedating drugs should also be avoided. (See "Use of opioids in the management of chronic pain in adults", section on 'Drug interactions'.)
While all patients should periodically be considered for opioid dose reduction, benefits of opioids may outweigh risks for those selected patients with persistent severe chronic pain despite adherence to nondrug and nonopioid therapies, including compliance with primary disease modifying therapies. In the authors' experience, examples include persistent or recurrently severe nociceptive pain conditions (eg, inflammatory arthritis, inflammatory bowel disorders, sickle cell-related pain) and inflammatory or injury-related neuropathic pain (eg, autoimmune demyelinating disorders, spinal cord injury, and occasionally phantom pain and complex regional pain syndrome [CRPS]). These disorders are discussed in other UpToDate topics on these conditions.
Opioid tapering and possible discontinuation may be considered periodically even for patients who have been on a stable dose, to minimize the development of complex persistent dependence, and reduce opioid related risks, especially in older adults. Indications for opioid tapering, risks of tapering, and the tapering process, are discussed in detail separately. (See "Opioid tapering for patients with chronic pain".)
INFUSION THERAPIES
Ketamine — Ketamine infusion has long been used for acute pain for inpatients and is increasingly used as an intravenous infusion for complex regional pain syndrome (CRPS), neuropathic pain, and other intractable chronic pain disorders. While there are no high-quality data to support ketamine infusions, the available data suggest that infusions given for several hours repeated over several days may have the potential to provide weeks to months of relief [125-128], with the best evidence of efficacy in CRPS and neuropathic pain patients. (See "Complex regional pain syndrome in adults: Treatment, prognosis, and prevention", section on 'Less favorable risk:benefit ratio'.)
Most studies of the efficacy of ketamine for chronic pain measure pain intensity as a primary outcome. However, ketamine is used for treatment-resistant unipolar depression and suicidal ideation, and it is possible that improved mood may contribute to improved pain scores in patients who receive ketamine for chronic pain. (See "Ketamine and esketamine for treating unipolar depression in adults: Administration, efficacy, and adverse effects".)
There are several reports of hepatobiliary dysfunction after recurrent ketamine administration [129-131]. In 2020 this prompted an FDA label change (updated in 2021) for ketamine, recommending that liver function tests should be checked before starting therapy, and periodically for those receiving recurrent therapy.
The published patient selection criteria and protocols for context, infusion-dose, duration, and frequency are quite variable and not standardized making it difficult to provide specific suggestions for infusion regimens, patient selection, or adjuvant therapies. We feel that if ketamine is used it should be part of a comprehensive treatment plan, rather than a standalone therapy.
Lidocaine infusion — Intravenous lidocaine infusion is used for multimodal analgesia for perioperative pain. (See "Nonopioid pharmacotherapy for acute pain in adults", section on 'Intravenous lidocaine'.)
It has also been used to treat chronic neuropathic pain, though the evidence supporting its use is not strong [132]. (See "Trigeminal neuralgia", section on 'Acute rescue therapy for patients with breakthrough pain'.)
Lidocaine infusion should be reserved for patients who have not responded to other treatments. In outpatient settings doses of 3 to 5 mg/kg administered over 30 to 60 minutes can relieve neuropathic pain short term, with sustained analgesia in some patients [132,133]. A positive response to intravenous (IV) lidocaine is sometimes viewed as an indication to proceed with other sodium channel blocking agents (such as mexiletine or some of the antiseizure medications) but the data to support this approach is lacking). Optimal doses, administration regimens, and patient selection have not been determined [134].
SPECIAL CONSIDERATIONS FOR PATIENTS WITH CANCER —
The pharmacologic management of pain in patients with cancer requires a stepwise approach that includes both opioid and nonopioid drugs. Mild or episodic pain can initially be managed with non-opioid analgesics (eg, acetaminophen or a nonsteroidal anti-inflammatory drug [NSAID]) with or without an analgesic adjuvant, with consideration of the risk of side effects and toxicities. Moderate to severe pain will likely require an opioid in addition to nonopioid analgesics, adjuvants, and tumor directed therapy when applicable [135]. Interventional therapies, such as intrathecal drug delivery systems and neuromodulation or ablation may also be considered when other approaches are insufficient or ineffective. (See "Overview of cancer pain syndromes".)
While the pharmacologic management of pain in patients with cancer is similar to that in patients without cancer, some special considerations apply to patients with cancer [136,137].
●Twenty to forty percent of cancer patients will have neuropathic pain, as a result of the tumor itself, cancer treatment (ie, radiation, chemotherapy, surgery) or related disease (eg, Herpes Zoster) [136].
●In patients with pain related to certain types of chemotherapy or targeted therapy, serotonin-norepinephrine reuptake inhibitors (SNRIs) can be helpful. As an example, duloxetine is effective for chemotherapy induced peripheral neuropathy associated with taxanes or platinum agents [138], and for musculoskeletal syndrome associated with aromatase inhibitors used for breast cancer. (See "Managing the side effects of tamoxifen and aromatase inhibitors", section on 'Musculoskeletal pains and stiffness' and "Prevention and treatment of chemotherapy-induced peripheral neuropathy".)
●In patients with chronic cancer pain that is poorly responsive to opioid therapy and a depressed mood, we often trial an antidepressant in addition to continuing other analgesics. We prefer SNRIs over tricyclic antidepressants (TCAs) given the more favorable side effect profile. If fatigue or somnolence is present, we will often try bupropion given its activating effects. (See "Patients with cancer: Clinical features, assessment, and diagnosis of unipolar depressive disorders".)
●In patients with new or increasing pain in addition to adjusting their treatment to address the increased pain burden, the threshold for new imaging and other diagnostic studies is much lower in cancer-related pain. All new or increasing pain should be evaluated and disease progression should be considered foremost as an explanation. (See "Overview of cancer pain syndromes".)
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: Chronic pain management".)
SUMMARY AND RECOMMENDATIONS
●Plan for treatment – Effective treatment of pain requires multimodal analgesia with an emphasis on non-drug modalities (eg, self-management, behavioral health support and physical therapy). When necessary, we add multi-targeted pharmacologic therapies (algorithm 1). (See "Approach to the management of chronic non-cancer pain in adults", section on 'Creating a plan for treatment'.)
●Type of pain – The choice of pharmacologic therapy depends on the type of chronic pain syndrome. In particular, nociceptive pain should be distinguished from neuropathic pain and nociplastic pain since treatments differ (table 1 and table 2 and algorithm 1). (See 'General principles of drug selection' above.)
The following general approach can be useful for a variety of specific causes of chronic pain. Recommendations for pharmacologic treatment for specific chronic pain conditions appear in topics on those conditions.
•Patients with nociceptive pain – For these patients the choice of pharmacologic therapy depends partly on the location of the pain, and also on patient co-occurring conditions. Oral or topical nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line therapy for many chronic nociceptive pain conditions (table 7). If usual treatment is ineffective for patients who are thought to have predominantly nociceptive pain, the patient may have neuropathic or nociplastic pain, which should also be treated. (See 'Pharmacologic therapy for nociceptive pain' above.)
•Patients with neuropathic pain – For these patients initial treatment usually involves antidepressants (ie, tricyclic antidepressants [TCAs], serotonin-norepinephrine reuptake inhibitors [SNRIs]), or antiseizure medications (gabapentin or pregabalin), with adjunctive topical therapy (eg, topical lidocaine, 8% capsaicin patch) when pain is localized (table 4). The choice among treatments should be based on the pain condition (if known), co-occurring conditions, medication side effects, cost, and patient values and preferences (table 6). (See 'Pharmacologic therapy for neuropathic or nociplastic pain' above.)
•Patients with nociplastic pain – For patients with nociplastic pain (table 1), careful and systematic mixed combinations of neuropathic drug treatments may be helpful alongside enhanced emphasis on nondrug treatment options (eg, cognitive behavioral therapy, physical activation). (See 'Pharmacologic therapy for neuropathic or nociplastic pain' above.)
●Antidepressants – TCAs and SNRIs are among the first-line treatment options for many chronic pain conditions, independent of their antidepressant effects (algorithm 1). Analgesic effects may require two to four weeks for maximal effect. These drugs have a variety of adverse effects which may limit their use (table 8). (See 'Antidepressants' above.)
Selective serotonin reuptake inhibitors (SSRIs) are not first-line treatment for any chronic pain condition.
•TCAs – Nortriptyline is our preferred initial TCA since it is less sedating and with fewer anticholinergic side effects than amitriptyline. Nortriptyline, amitriptyline, doxepin, imipramine, and desipramine are used for chronic pain. Amitriptyline is the most sedating of these drugs. (See 'Tricyclic antidepressants' above.)
•SNRIs – Duloxetine, venlafaxine, and milnacipran are used for a variety of types of chronic pain. Duloxetine has the strongest evidence base for benefit. (See 'Serotonin-norepinephrine reuptake inhibitors' above.)
●Antiseizure medications – Antiseizure medications are among the first line therapies for some forms of neuropathic or nociplastic pain (algorithm 1).
•Gabapentinoids – Gabapentin and pregabalin are among the first line therapies for painful diabetic neuropathy, and may also be used for postherpetic neuralgia. Of note, these drugs are associated with respiratory depression in older adults and in patients who receive other sedatives or opioids, and there is potential for misuse. (See 'Gabapentin and pregabalin' above and "Management of diabetic neuropathy", section on 'Choice of agent' and "Postherpetic neuralgia", section on 'Initial pharmacotherapy'.)
•Other antiseizure medications – Carbamazepine or oxcarbazepine are initial treatments for trigeminal neuralgia. (See 'Other antiseizure medications' above.)
●Adjuvant medications – Topical lidocaine or capsaicin and cannabinoids may be beneficial in some patients (algorithm 1). We avoid the use of muscle relaxants (eg, tizanidine, cyclobenzaprine, carisoprodol) and benzodiazepines in patients with chronic pain. (See 'Other adjuvant medications' above.)
●Opioids – Opioids should be used on a chronic basis only in patients who are assessed to be at low risk for substance use disorder, who have persistent severe pain despite trials of nonopioid analgesics and antidepressants or antiseizure medications, and in whom the potential benefits outweigh the risks. (See 'Opioids' above and "Use of opioids in the management of chronic pain in adults".)
Opioids should always be combined with nonpharmacologic and often nonopioid pharmacologic therapy, and should be carefully monitored for sustained analgesic and functional benefit, risk, and treatment adherence. (See 'Opioids' above.)
The risks, side effects, and benefits of continuing opioid therapy should be assessed on a regular basis. (See 'Opioids' above and "Opioid tapering for patients with chronic pain".)
●Emerging therapies – Ketamine and lidocaine infusion are emerging therapies with mixed results for chronic pain. Optimal doses, administration regimens, and patient selection, have not been determined. (See 'Infusion therapies' above.)
