Coanalgesics for Chronic Pain Therapy:

Coanalgesics are medications whose initial development and primary indications were for conditions other than pain. However, many have since been found to contribute significantly to pain relief when prescribed alone or in combination with other analgesics. Coanalgesics comprise a wide variety of drug classes including but not limited to antidepressants, anticonvulsants, local anesthetics, and skeletal muscle relaxants. These medications may enhance the effects of opioid analgesics or nonsteroidal anti-inflammatory drugs (NSAIDs), have independent analgesic activity in certain painful conditions, or counteract the adverse effects of some analgesics. Coanalgesics are frequently added to an opioid to enhance pain relief, address refractory pain, and allow lower doses of opioids to reduce their adverse effects, especially in patients with cancer-related pain.¹ However, for neuropathic pain and other chronic noncancer pain conditions, coanalgesics are being used more commonly as the primary analgesic.

Given that coanalgesics are associated with their own set of adverse effects and patients may already be taking several medications for pain and other medical conditions, coanalgesics are typically indicated for unsatisfactory pain relief from primary analgesics (ie, acetaminophen, NSAIDs, and opioids). A recent edition of an analgesic guide published by the American Pain Society for clinicians outlined the uses of various coanalgesics in detail²; however, some noteworthy advances in chronic pain management have occurred since its publication. The goals of this article are to highlight coanalgesic treatment options that are currently available to patients with chronic pain as well as provide guidelines for their use in clinical care.

We conducted a comprehensive literature search of original research and review articles published from 1980 to June 2011 using the PubMed and Medline databases for each of the common coanalgesic drug classes (ie, antidepressants, anticonvulsants, topical analgesics, and skeletal muscle relaxants) as well as their subcategories and respective abbreviations when applicable (tricyclic antidepressants [TCAs], selective norepinephrine reuptake inhibitors [SNRIs], and selective serotonin reuptake inhibitors [SSRIs]). Individual medications were also searched, and all of the above terms were combined with the search terms “pain,” “chronic pain,” “neuropathic pain,” “neuropathy,” “osteoarthritis,” and “fibromyalgia.” In addition, the terms “coanalgesics” and “adjuvant analgesics” were used. The references and related citations for the resulting articles also were reviewed for pertinence. Additional articles and in-progress studies were identified via www.ClinicalTrials.gov. To complement and update our previously published review on coanalgesics,² we systematically searched for significant randomized, controlled, open-label studies as well as systematic reviews and meta-analyses that had been published from 2005 to 2011 to be included in this review. Case reports and case series were excluded.

Antidepressants may serve multiple roles in pain management. According to the monoamine hypothesis, they act by blocking the presynaptic reuptake of serotonin and/or norepinephrine in the central nervous system, thus enhancing the action of the descending inhibitory pain pathways. Other theorized mechanisms of action include neuron membrane stabilization through inhibition of sodium channels and inhibition of neuronal hyperexcitability through N-methyl-D-aspartic acid (NMDA) antagonist-like effect. In addition to their analgesic effects, they can be used to treat concurrent symptoms that exacerbate pain, such as depression, anxiety, and insomnia.

Tricyclic antidepressants have the strongest evidence base of all the coanalgesics. Several systematic reviews and meta-analyses have concluded that TCAs are effective for fibromyalgia³ and multiple types of neuropathic pain, including postherpetic neuralgia and painful diabetic peripheral neuropathy, regardless of whether patients have concurrent depression.⁴ Evidence also supports the use of TCAs for chronic low back pain.⁵

Tricyclic antidepressants are frequently used to treat neuropathic pain caused by surgical trauma, radiation therapy, chemotherapy, or malignant nerve infiltration.⁶ One small double-blind randomized controlled trial investigated amitriptyline therapy for chemotherapy-induced neuropathy, but did not find an appreciable reduction in symptoms.⁷ Aside from this study, no controlled studies have been conducted in these conditions. Despite limited evidence of the effectiveness of TCAs for cancer pain, a few studies support their use in this patient population.^8-10

Because TCAs are effective, inexpensive, and usually dosed only once daily for pain, clinicians should consider TCAs as initial therapy for neuropathic pain, assuming that there are no relative contraindications (ie, ischemic heart disease, heart failure, conduction disorders, and arrhythmias) to their use.¹¹ Patients prescribed TCAs should be closely monitored for adverse effects, such as cardiotoxicity, confusion, urinary retention, orthostatic hypotension, nightmares, weight gain, drowsiness, dry mouth, and constipation.¹² According to a panel of pain experts, a screening electrocardiogram (ECG) is recommended before beginning TCA treatment in patients aged ≥ 40 years to evaluate for conduction abnormalities.¹³

Secondary amine TCAs (nortriptyline and desipramine) are preferred because they are better tolerated than the tertiary amine TCAs (amitriptyline and imipramine) but have comparable analgesic efficacy.^14-16 Goudas et al¹⁷ performed a comprehensive review, including meta-analytic methods, of the efficacy and safety of TCAs in cancer pain. Sedation and orthostatic hypotension are common adverse effects and may limit the concomitant use of opioid analgesics. According to Beers,¹⁸ amitriptyline should be avoided in older adults (aged ≥ 65 years) because of the frequent occurrence of anticholinergic adverse effects (ie, dry mouth, orthostatic hypotension, constipation, and delirium) and potential exacerbation of cognitive impairment and gait disturbances that may predispose older patients to falls and the risk of hip fractures.

The analgesic effects of TCAs are usually seen at lower adult doses (25–100 mg/day) than the commonly recommended antidepressant doses (150–300 mg/day). In addition, pain response may be seen within 5 to 7 days. A common regimen is starting with 10 mg at bedtime for patients who weigh > 50 kg and older adults. The dose is increased approximately every 7 days depending on any emergent adverse effects and until the desired effect is obtained, up to a maximum of 100 mg to 150 mg in adults. For patients unable to take tablets, nortriptyline is available in liquid form.

Administration of TCAs at bedtime promotes sleep and minimizes daytime side effects. However, patients should be cautioned about nocturnal orthostatic hypotension. Nortriptyline and desipramine may cause somewhat less orthostatic hypotension than other TCAs. Because of the potential for lethal cardiotoxicity, TCAs should be used cautiously in patients at risk for suicide or accidental death from overdose.¹⁹

The newer SNRI antidepressants have fewer adverse effects and are usually better tolerated than TCAs. Venlafaxine inhibits presynaptic uptake of serotonin at lower adult doses (75 mg/day) and both serotonin and norepinephrine at higher doses (150–225 mg/day).¹⁹ It also has some NMDA antagonistic activity and the capacity to block sodium channels.²⁰ Venlafaxine is structurally similar to tramadol, an opioid agonist, and has been shown to modulate allodynia and hyperalgesia in human experimental pain models.¹² At least 2 randomized clinical trials have demonstrated venlafaxine’s analgesic benefit at doses of 150 to 225 mg/day in patients with painful polyneuropathy²¹ and painful diabetic peripheral neuropathy.²² One recent small single-blind placebo-controlled study found venlafaxine to be effective for osteoarthritis (OA).²³ Mixed or negative study results for the following have been observed in other populations: 1) postmastectomy pain,²⁴ 2) postherpetic neuralgia,²⁵ and 3) various peripheral and central neuropathic pain conditions.²⁶ Two of these studies^24,26 used lower doses, which might explain lack of benefit.¹⁹

In terms of safety, venlafaxine is better tolerated than TCAs and lacks the anticholinergic or antihistamine effects seen with TCA use. However, in 1 study,²² 5% of venlafaxine-treated patients developed ECG changes. Therefore, ECG monitoring is recommended in patients with cardiovascular risk factors (ie, diabetes mellitus, hypertension, hypercholesterolemia, and current smoker).¹⁹ Two to 4 weeks are frequently needed to establish the effective dose of venlafaxine, and patients should be tapered gradually (for 2 weeks) to prevent “discontinuation syndrome,”^27,28 which is characterized by multiple symptoms, such as insomnia, diarrhea, nausea, headaches, lethargy, irritability, dizziness, and paresthesias.

Duloxetine is approved by the US Food and Drug Administration (FDA) for the treatment of pain due to diabetic neuropathy and fibromyalgia, as well as the treatment of chronic low back pain. Three randomized controlled trials of patients with painful diabetic peripheral neuropathy have demonstrated duloxetine’s efficacy compared with placebo.^29-31 A 52-week open-label study³² and a meta-analysis of several randomized controlled trials that evaluated cardiovascular risks relative to placebo (ie, abnormal ECGs)³³ demonstrated the safety of duloxetine. Three double-blinded, placebo-controlled trials have also established the efficacy of duloxetine in fibromyalgia.³³ Duloxetine is expected to be safer than TCAs¹⁹ and is generally well tolerated; however, instances of discontinuation syndrome have been reported.³⁴ The most common adverse effect is nausea. Furthermore, dosing of duloxetine is simple (30 mg/day or 60 mg/day) relative to TCAs or anticonvulsants.

Milnacipran is a newer coanalgesic that is FDA approved for the treatment of fibromyalgia. Two key clinical trials led to this decision, during which the multiple symptoms associated with this disorder (eg, fatigue, sleep disturbances, diminished physical, and mental function) in addition to pain were evaluated.^35,36 Milnacipran use significantly improved all of these symptoms except sleep disturbances, and the most common adverse effects were headache and nausea.³⁷ Current studies show these improvements continued for at least 1 year.³⁸ The usual daily dose is 100 mg/day, which may be increased to 200 mg/day depending on response.

Selective serotonin reuptake inhibitors are similar to SNRIs in their safety profile and tolerability; however, limited data exist to support their use as analgesics. While fluoxetine was shown to improve pain in animal models, it was not effective in a clinical trial of neuropathy.¹⁴ A recent systematic review concluded that citalopram was ineffective for fibromyalgia.³⁹ Sindrup et al^40,41 have conducted 2 separate studies showing the efficacy of paroxetine and citalopram in patients with diabetic peripheral neuropathy. Escitalopram has recently been shown to have comparable results to duloxetine for the treatment of chronic low back pain.⁴² The results of this study were encouraging; however, further confirmation of these findings is warranted due to the open-label design of the study and lack of a placebo control. The main indication for the treatment with an SSRI is concurrent depression, anxiety, or insomnia; all are commonly associated with chronic pain. Because of TCAs’ adverse effects at higher doses, clinicians commonly use low doses for neuropathic pain in addition to a regular dose (ie, 20 mg/day) of SSRIs for patients with concurrent depression.

Anticonvulsants are frequently used to treat neuropathic pain and other pain conditions, such as migraine headaches. Anticonvulsants, also known as antiepileptic drugs (AEDs), constitute a diverse class with several different mechanisms of action that have been used in pain medicine for decades. Their primary action is produced by dampening neuronal excitability through the reduction of ectopic, spontaneous firing of cortical neurons that cause seizures. Therefore, it is logical that anticonvulsants might also decrease spontaneous firing of sensory neurons after nerve injury and the subsequent development of neuropathic pain and sensitization (ie, reduced pain thresholds).

Anticonvulsants can be added to TCAs for patients in whom TCAs alone are inadequate to manage neuropathic pain. Anticonvulsants also may be used as first-line analgesics in patients unable to tolerate TCAs and appear to have similar efficacy. In a recent randomized, double-blind, active placebo-controlled, crossover trial,⁴³ patients were randomized to active placebo (lorazepam), controlled-release morphine, gabapentin, and a combination of gabapentin and morphine for 5 weeks. The study showed that the combination of morphine and gabapentin provided the best analgesia and that each medication was administered at lower doses than when given as a single treatment.⁴³

The older anticonvulsants are generally associated with a greater incidence of adverse effects and are therefore relegated to second- or third-line status. Among these drugs, the strength of evidence is best for carbamazepine and phenytoin. In addition, valproate and clonazepam have been used clinically for many years. Carbamazepine is effective for trigeminal neuralgia, painful diabetic neuropathy, postherpetic neuralgia, and central poststroke pain,⁴⁴ and phenytoin has been used in cancer pain.⁴⁵ Valproate has been shown to be effective for diabetic neuropathy and postherpetic neuropathy,^46-48 but was not effective in a study of painful polyneuropathies.⁴⁹ A meta-analysis evaluated 23 randomized trials of 5 anticonvulsants: carbamazepine, gabapentin, phenytoin, clonazepam, and valproate⁵⁰ for the management of pain. Most of the trials involved chronic nonmalignant pain; only 1 trial evaluated cancer pain, and 1 involved postoperative pain. This meta-analysis concluded anticonvulsants were effective for trigeminal neuralgia and may be used to treat other chronic pain syndromes if response to other medications is inadequate.

Several newer anticonvulsants (eg, lamotrigine, topiramate, zonisamide, and levetiracetam) have been studied for a variety of pain conditions, especially primary headaches.⁵¹ Lamotrigine has shown benefit in a small crossover clinical trial of patients with refractory trigeminal neuralgia⁵²; however, no follow-up studies have been completed to date. It is considered a second-line defense for this condition and is potentially beneficial for pain associated with diabetic neuropathy, multiple sclerosis, spinal cord injury, central poststroke pain, polyneuropathy, and complex regional pain syndrome.^12,53-55 Lamotrigine requires a slow dose titration due to its associated adverse effects, such as somnolence, dizziness, and ataxia.¹ Clinicians also should be aware of the rare, but potentially critical risk of developing a severe rash, known as Stevens-Johnson syndrome, associated with its use.

Topiramate has shown mixed results. It was demonstrated to be beneficial in a randomized controlled trial of patients with painful diabetic peripheral neuropathy⁵⁶ but not helpful in 3 other trials of diabetic neuropathy.⁵⁷ Topiramate has also been used clinically for complex regional pain syndrome type 1; however, trials are not available. Topiramate may cause hyperchloremic, non-anion gap metabolic acidosis (decreased serum bicarbonate). Therefore, measurement of baseline and periodic serum bicarbonate during topiramate treatment is recommended. Data for tiagabine, zonisamide, and levetiracetam are limited but may show analgesic benefit.¹

Gabapentin has become a first-line treatment for various neuropathic pain conditions due to its proven effectiveness, favorable adverse effect profile, and lack of major drug interactions.^58-60 Gabapentin and pregabalin modulate cellular calcium influx into nociceptive neurons by binding to voltage-gated calcium channels, specifically the alpha-2-delta subunit of the channel,^61,62 thus reducing the release of glutamate, norepinephrine, and substance P. Multiple randomized controlled trials have shown greater pain relief with gabapentin versus placebo in pain states associated with postherpetic neuralgia, painful diabetic peripheral neuropathy, phantom limb syndrome, Guillain-Barré syndrome, cancer, and acute and chronic spinal cord injury.⁶³ In some trials, secondary benefits from gabapentin were observed in sleep, mood, and health-related quality of life.^19,64 On the other hand, studies of patients with painful human immunodeficiency virus (HIV) neuropathy⁶⁵ and chemotherapy-induced neuropathy⁶⁶ did not show a benefit from gabapentin treatment.

Only a few head-to-head and combination-therapy trials have also been conducted with gabapentin. A double-blinded, non–placebo-controlled effectiveness trial comparing gabapentin with nortriptyline for postherpetic neuropathy found both to be equally effective and with fewer adverse effects experienced by patients randomized to the gabapentin arm.⁶⁷ Gabapentin was also evaluated in combination with nortriptyline for both painful diabetic and postherpetic neuropathies, and was found to be more effective than either medication alone.⁶⁸ Despite these and other relevant findings, a recent meta-analysis concluded that the available head-to-head studies were not adequately powered to differentiate between the efficacy of gabapentin and TCAs for these neuropathies.⁶⁹

Gabapentin is usually started at 100 mg to 300 mg at bedtime and can be titrated every 3 days until an effective dose of 1800 mg to 3600 mg/day is reached. Titration may take several weeks to reach the higher doses. Gabapentin is typically dosed 3 times daily for neuropathic pain. The most common adverse effects are somnolence, dizziness, ataxia, fatigue, impaired concentration, and peripheral edema. These adverse effects usually occur early in the course of treatment. Certain patients, especially older adults and those with complex medical illness, may need slower escalations of gabapentin.⁷⁰ Doses should be reduced in those with renal impairment.

Pregabalin, a derivative of gabapentin, is a relatively new anticonvulsant in clinical practice. It is the first FDA-approved medication for fibromyalgia, and has strong evidence of analgesic efficacy. Multiple placebo-controlled, randomized trials of pregabalin have showed efficacy in a variety of neuropathic pain conditions.^71-74 The adverse effects, tolerability, and lack of significant drug interactions are similar for pregabalin and gabapentin, although pregabalin is also associated with weight gain and cognitive effects.⁷⁵ However, given the recent release of pregabalin, its long-term safety is not as well established as for gabapentin.¹⁹ Pregabalin may be started at 75 mg to 150 mg/day (in either 2 or 3 divided doses) and reduced in patients with renal impairment. Pain relief may be more rapid with pregabalin relative to gabapentin because therapeutic doses can be initiated early in treatment with pregabalin (150 mg/day)¹³ and uptitrated more quickly to a maximum dosage of 300 mg to 600 mg/day. Of note, pregabalin was found to have anxiolytic benefits in a randomized controlled trial of patients with generalized anxiety disorder.⁷⁶

Topical local anesthetics may be useful in pain treatment and are available in oral, gel, cream, patch, and iontophoresis forms. These medications are thought to work by decreasing neuronal excitability at sodium channels that propagate action potentials. While theoretically useful to apply over large areas of the body for neuropathic pain, their use in this way is limited by their relatively high costs and risk of toxicity.¹

The topical lidocaine 5% patch is FDA approved for postherpetic neuralgia and has been used successfully in a variety of neuropathic pain syndromes, including diabetic neuropathy, complex regional pain syndrome, postmastectomy pain, and HIV-related neuropathy.^77,78 Randomized trials have documented the efficacy of transdermal lidocaine in reducing pain compared with placebo patches in patients with postherpetic neuralgia^79,80 and diverse neuropathic conditions (eg, mononeuropathies and intercostal and ilioinguinal neuralgia).⁸¹ Lidocaine 5% has also been shown to improve quality of life in patients with postherpetic neuralgia.⁸⁰

Lidocaine patches are normally worn for up to 12 hours and then removed for 12 hours. This dosage form has an excellent safety profile regardless of how many patches are used. Systemically active serum levels of lidocaine are minimal.⁸² The patches may be cut to the size of the affected area, and up to 3 patches a day may be used. Transdermal lidocaine can be used as adjunctive therapy for neuropathic pain, especially for small, localized areas, and may help avoid systemic side effects from other medications. The most common adverse effects are mild skin redness, rash, or application-site irritation. Because a significant amount of medication can be contained in the patch after use, these patches should be discarded properly. Topical lidocaine gel was found to be helpful for postherpetic neuropathy⁸³ but not HIV neuropathy.⁸⁴

Capsaicin is an enzyme found in all hot peppers. When applied topically, it depletes the pain mediator substance P from afferent nociceptive neurons. Cream and solution formulations have been used effectively in peripheral neuropathic pain and arthritic pain. These nonprescription formulations are most useful as adjuncts (not monotherapy). Capsaicin cream is available over the counter and is available in both low (0.025%) and high (0.075%) concentrations. It has been shown to be effective in reducing neuropathic postoperative pain after mastectomy⁸⁵ as well as for arthritis pain.^86,87 A systematic review and a recent randomized trial of capsaicin versus placebo found mixed results in patients with painful diabetic peripheral neuropathy, postherpetic neuropathy, and HIV-related neuropathy.⁸⁸

Capsaicin cream and solution preparations must be applied to the affected area 3 to 4 times daily and normally requires several weeks of therapy for effective pain relief. Initially, capsaicin may cause local burning that can be severe. Most patients develop tolerance to the burning after a few days of therapy. Caution patients to wash their hands thoroughly after applying capsaicin and to keep it away from eyes and mucous membranes. The analgesic effect is dose dependent and may last for several weeks after the last application.¹² To enhance adherence and tolerability, a full container of the lower strength should be used before trying the higher concentration. Some patients tolerate capsaicin better if its application is preceded by a topical local anesthetic.

A new transdermal patch 8% capsaicin formulation was FDA approved for treatment of postherpetic neuralgia following 2 randomized clinical trials that demonstrated its effectiveness.^89,90 Both trials found that a single, 60-minute application provided significant pain relief compared with placebo at 2 weeks, which lasted for the duration of the 12-week studies.^89,90 This formulation has also shown to be effective for HIV-related neuropathy.⁹¹ The most common adverse effects were temporary erythema, pain and papules at the application site, and transient pain-related blood pressure elevations occurred in some patients immediately after application. A topical anesthetic may lessen the discomfort of the application, as with lower concentrations of capsaicin. It is only available by prescription, and it is recommended that 8% capsaicin be administered by a physician or health care professional. It can be reapplied after 3 months, if necessary. A recent 1-year investigation into the safety of the 8% capsaicin patch in patients with postherpetic neuropathy and HIV-related neuropathy found no additional adverse effects associated with long-term use.⁹¹ Topical analgesic balms (creams and solutions containing topical agents that increase local blood supply and produce a feeling of warmth [eg, menthol, camphor, and methyl salicylate]) act as counterirritants. While there is no clear evidence of the efficacy of these agents, their safety risk is minimal. Some patients also report relief from rubbing or massaging action when they apply balms to painful areas.

Numerous anti-inflammatory drugs have been studied for topical use in patients with neuropathic pain, and results have been mixed.¹² For clinical use, 3 reviews have concluded that topical NSAIDs are effective pain relievers for musculoskeletal and soft tissue pain and pain related to a variety of rheumatic diseases.^92-94 These medications are not available as proprietary drugs in the United States and need to be compounded by pharmacists for clinical use. However, 1 relatively new topical NSAID, diclofenac sodium 1% gel, has been studied in clinical trials⁹⁵ and was FDA approved for OA.

While topical nitrates are usually considered in the context of ischemic heart disease, preliminary data suggest that nitrates have potent analgesic and anti-inflammatory effects⁹⁶ mediated by nitric oxide release. Topical nitrate in the form of glyceryl trinitrate (GTN) was shown to reduce pain related to tendonitis⁹⁷ and OA.⁹⁸ Enhanced pain relief and tolerability was found when GTN was combined with 0.025% capsaicin.⁹⁸ In addition, 3 reports suggest that topical nitrates may potentiate opioid effects in the postoperative setting and for cancer pain management.^99-101 Headache is the most common adverse effect (50%–60%) from topical nitrate use, but the medication is generally well tolerated.

Mexiletine, an oral anesthetic and sodium channel blocker, is not especially useful for the treatment of neuropathic pain due to modest efficacy and frequent adverse effects (eg, diarrhea and nausea), especially at higher dosages. In 1 study, almost half of patients on mexiletine discontinued the treatment because of side effects.¹⁰² Furthermore, mexiletine is contraindicated in patients with second- or third-degree heart block.¹² Mexiletine was shown to be only modestly effective for pain relief or to have no benefit in 3 randomized controlled trials in patients with painful diabetic peripheral neuropathy and other neuropathic conditions.^103-105 It may be considered as a third-line therapy in patients who do not respond to antidepressants and anticonvulsants.

A systematic review by Chou¹⁰⁶ concluded that there was “fair evidence” that cyclobenzaprine, carisoprodol, orphenadrine, and tizanidine are effective compared with placebo in patients with musculoskeletal conditions, primarily acute back or neck pain. There is little evidence to support the use of muscle relaxants for chronic low back pain. Cyclobenzaprine is the best studied of the muscle relaxants and is structurally related to TCAs. A recent review found there was evidence to support its use in the treatment of fibromyalgia, but that its efficacy was not significantly different from amitriptyline or nortriptyline.¹⁰⁷

Tizanidine is a relatively short-acting, oral alpha-2 agonist that is classified as a muscle relaxant. While tizanidine has primarily been used to treat spasticity, some studies suggest that tizanidine can be effective for tension-type headache, neuropathic pain, trigeminal neuralgia, and myofascial pain.^108-111 In pharmacokinetic studies in which tizanidine was coadministered with either fluvoxamine or ciprofloxacin (CYP1A2 inhibitors), the serum concentration of tizanidine was significantly increased and potentiated its hypotensive and sedative effects.

Muscle relaxants’ analgesic effects appear nonspecific. No evidence exists that they actually relax skeletal muscles.¹ Commonly, after more than 1 to 2 weeks of use, these drugs produce more central than skeletal muscle relaxant activity, which may lead to physical dependence. The most common adverse effect of these medications is sedation, which can be additive to opioids and other centrally acting medications (eg, TCAs and SNRIs). Therefore, treatment should be initiated at low doses and monitored carefully.

Botulinum toxin reduces the release of substance P and vanilloid receptors (eg, TRPV1). It has been used clinically for a variety of pain disorders, including headaches, musculoskeletal pain, interstitial cystitis, and vulvodynia, despite sparse clinical trial data. It can be considered for persistent pain secondary to muscle spasms. Recent clinical trials have investigated its efficacy in peripheral neuropathic pain¹¹² and refractory shoulder pain¹¹³ with positive results.

The most common antispasmodic agent used as an adjunct to analgesics is baclofen, which can be administered either orally or intrathecally. Baclofen is an agonist of the inhibitory neurotransmitter gamma-amino-butyric acid (GABA) that acts specifically at GABA_B receptors. Baclofen is a potent antispasmodic that may produce analgesia in neuropathic pain¹¹⁴ and possibly trigeminal neuralgia,¹¹⁵ although the small sample size and design of the trials in trigeminal neuralgia patients hinder interpretation of the evidence.¹¹⁶ Baclofen has been used in combination with carbamazepine for trigeminal neuralgia and given intrathecally to relieve intractable spasticity and neuropathic pain that did not respond to opioids. If used, patients should be started at 5 mg/day and slowly titrated to optimal effect. Most patients will usually require 20 mg/day to > 200 mg/day to achieve optimal effect. The most common adverse effects are weakness, sedation, hypotension, and confusion. To avoid severe withdrawal symptoms and the potential for seizures, baclofen should be discontinued gradually.

A few new gabapentin clinical trials are underway, including its comparison with amitriptyline in the treatment of pediatric neuropathies (NCT00312260) and its combined effect with duloxetine and donepezil on painful diabetic neuropathy and chronic low back pain (NCT00619983). Various formulations of topical capsaicin also continue to be studied for chronic neck pain (NCT01200745) and diabetic neuropathy (NCT00993070, NCT01125215).

Chronic pain is still inadequately treated in many people. In summary, coanalgesic therapy should be considered under the following conditions:¹²

• The toxic limit of primary analgesics (NSAIDs, opioids) has been reached.

• The therapeutic benefit of a primary analgesic has reached a plateau.

• Opioid use is contraindicated because of active substance use disorder or aberrant behaviors.

• Individual variation in response to medications varies substantially. Patients often convey that different medications will impart distinct analgesic benefits. Therefore, several different medications may be tried to find the greatest pain relief with the least side effects.

The emergence of new analgesic indications for existing drugs provides additional options for clinicians caring for these patients. Table 1 provides the dosing information for the medication classes presented in this article. Anticonvulsants are useful in treating various neuropathic pain conditions and gabapentin is recommend as a first-line agent due to its safety profile, efficacy demonstrated in clinical trials, and longer history.¹⁹ Other anticonvulsants may be tried in succession if there is minimal response or the use of gabapentin is contraindicated. However, due to a lack of comparative effectiveness trials that compare 2 medications, no distinctions in efficacy can be made among the second-line anticonvulsants.

Good evidence exists that antidepressants are analgesic, especially for neuropathic pain conditions and fibromyalgia. Concurrent pain and depression may also be managed with antidepressants. However, data are limited for their efficacy in cancer pain, although antidepressants may be used in cancer patients with neuropathy with suboptimal response to opioids¹¹⁷ or in combination with opioids, particularly for moderate-to-severe pain.¹ Other effective therapies include topical anesthetics for localized neuropathic pain, OA, and pain associated with complex regional pain syndrome. Select muscle relaxants may be effective for a range of disorders. However, little evidence exists for their use in patients with chronic low back pain.