Pharmacologic management of chronic neuropathic pain

Assessment and diagnosis of NeP.

Neuropathic pain can be mediated by central causes, such as stroke or multiple sclerosis, and by peripheral causes, such as diabetic neuropathy or surgical procedures. The patient’s history and physical examination findings are essential to diagnosing NeP. Some diagnoses based on history are obvious, such as shingles and diabetes mellitus preceding postherpetic neuralgia and painful diabetic neuropathy, respectively. Questionnaires have been developed to help differentiate between nociceptive pain and NeP. True weakness (different from pain-related or antalgic weakness), reduced or absent reflexes, allodynia, and hyperalgesia all favour a diagnosis of NeP. Often patients describe neuropathic pain as accompanied by sensations of burning, tingling, and electric jolts. Screening tools, such as the Douleur Neuropathique 4, the self-report Leeds Assessment of Neuropathic Symptoms and Signs, and the ID Pain questionnaire (Table 1), have been shown to be valid and reliable discriminators of NeP.^10–12 Electromyography and nerve conduction studies can provide evidence of nerve injury but might not be sensitive for small-fibre neuropathies. Guidelines are available to determine the diagnostic certainty of NeP.^13,14

CanMEDS–Family Medicine considerations.

Chronic pain conditions, such as NeP, require management by physicians using more than pharmacologic expertise. The CanMEDS–Family Medicine roles described by the College of Family Physicians of Canada serve as a framework for improving patient care.¹⁵ Specifically, as professionals, physicians must commit to regulated, ethical practice with high personal standards of behaviour. Being a scholar requires lifelong commitment to learning, creation, dissemination, and translation of medical pain knowledge. As family medicine experts, the knowledge is applied in a manner that places patients and families in the correct biopsychosocial-spiritual framework within their community. Patients with chronic pain experiencing NeP often describe this condition as severe and unrelenting, and it is often associated with comorbid anxiety and depression. As a communicator, the practitioner should facilitate the doctor-patient relationship through validation of the patient’s pain and communicate the treatment goals, such as improvement of sleep, physical functioning, and other elements of quality of life, and discuss pain reduction such that the pain might become “tolerable,” rather than promise the elimination of the pain condition. Patients should be made aware that chronic pain might be a lifelong condition. As a collaborator and leader, treatment goals can be realized by involving multidisciplinary teams (psychologists, physiotherapists, etc) to maximize nonpharmacologic adjunctive treatments. Family physicians serve as their patients’ main advocate within their communities, and help them to navigate the health care system.

First-line analgesics.

The first-line medications are the gabapentinoid class of anticonvulsants, TCAs, and SNRIs. There are positive results showing efficacy in painful diabetic neuropathy for all first-line analgesics.^16–19 In the context of postherpetic neuralgia, there has been proof of efficacy for gabapentinoids and TCAs.^16,18 Pregabalin has additionally been shown to have analgesic benefit in patients with chronic central NeP after spinal cord injury^20,21 and secondary benefit (improved sleep and reduced anxiety) in central poststroke pain.²² Tricyclic antidepressants have been shown to relieve pain in various NeP conditions.²³ Of the SNRIs, duloxetine has been found to have analgesic benefit in chemotherapy-induced painful neuropathy,²⁴ while gabapentin has been shown not to.²⁵ Additionally, high-dose venlafaxine has shown efficacy in mixed painful polyneuropathy.²⁶ In the context of idiopathic trigeminal neuralgia, an exception can be made for carbamazepine, which remains the first-choice analgesic.²⁷ Dosing guidelines for selected NeP analgesia agents can be found in Table 2.⁷

Tricyclic antidepressants are extensively studied, inexpensive, and administered daily. They inhibit the reuptake of serotonin and norepinephrine, block N-methyl-d-aspartate agonist–induced hyperalgesia, and block sodium channels.²⁸ When prescribing TCAs, secondary amines (nortriptyline, desipramine) are usually better tolerated in terms of sedation, postural hypotension, and anticholinergic effects when compared with tertiary amines (amitriptyline and imipramine) with comparable analgesic efficacy.²⁹ Side effects might also be reduced by starting at a lower dose, administration in the early evening, and titrating slowly. The analgesic effect of TCAs is independent of the antidepressant effect and the analgesic effect occurs at one-fifth to one-third of the dose required to treat depression.³⁰ In the geriatric population, TCAs might be deleterious, as they can impair cognition and increase the risk of falls.³¹ The updated American Geriatrics Society Beers criteria and version 2 of the STOPP/START (Screening Tool of Older People’s Prescriptions and Screening Tool to Alert to Right Treatment) criteria are useful references to minimize inappropriate prescribing in the elderly.^32,33 As TCAs have been associated with tachycardia and myocardial infarction (at doses above 100 mg daily), the Special Interest Group on Neuropathic Pain (NeuPSIG) recommends a baseline electrocardiogram in patients starting TCAs who are older than 40 years of age and are at risk of sudden cardiac death or who have a history of cardiovascular disease.³¹

Gabapentinoids lead to reduction of the influx of calcium in the terminals of primary afferent neurons entering the dorsal horn of the spinal cord.²⁸ Gabapentin and pregabalin are not hepatically metabolized, and they do not alter hepatic enzymes. As they are eliminated renally, dose adjustment is required in those with renal insufficiency or those who are undergoing dialysis.³⁴ Pregabalin can be taken twice a day and has more linear pharmacokinetics relative to gabapentin, which is taken 3 times a day. Somnolence, dizziness, edema, and weight gain are common side effects of gabapentinoids, and they might require low initial dosing and slow titration, especially in the elderly.³⁵

Serotonin-norepinephrine reuptake inhibitors inhibit the reuptake of serotonin and norepinephrine at neuronal junctions. Duloxetine and venlafaxine are the 2 most studied drugs within this class. A typical side effect of duloxetine and venlafaxine is nausea; other side effects such as elevated heart rate and blood pressure are less common. Gastrointestinal side effects are most common with venlafaxine. Hepatotoxicity has been reported with duloxetine. Duloxetine directly relieves painful physical symptoms, in addition to the pain relief from improved depressive symptoms over time.^35,36 There is 1 phase III clinical trial of desvenlafaxine in the setting of NeP; at interim analysis, randomization to a 400-mg daily dose was discontinued owing to a clear increase in adverse events.³⁷ Duloxetine inhibits serotonin to norepinephrine reuptake at a ratio of 9:1 while venlafaxine has a ratio of 30:1.³⁸ At low doses (< 200 mg daily), venlafaxine only inhibits serotonin.³⁹ There is evidence that combination pharmacotherapy with gabapentinoids and SNRIs can be helpful.³⁵ Duloxetine should be avoided in those with hepatic insufficiency and severe renal impairment; doses higher than 60 mg daily have not consistently shown benefit in clinical trials.⁴⁰ Tricyclic antidepressants, SNRIs, and selective serotonin reuptake inhibitors are all relatively contraindicated with concurrent use of monoamine oxidase inhibitors owing to the possibility of serotonin syndrome.⁴¹

If patients are appropriately identified as having NeP using standardized NeP tools, first-line medications are very effective early in the treatment process.⁴² The quality of the evidence provided above is high for SNRIs and gabapentinoids in the treatment of NeP, but moderate for TCAs if started before opioids.⁴² A reduction in pain of 20% to 30% should be considered a success. A change in a patient’s function, sleep pattern, or their ability to be social are key matters of evaluation rather than a pain numeric rating scale score. However, once opioid medications are entrenched, the effect sizes of these first-line medications tend to be minimized.

Second-line analgesics.

Tramadol is a second-line medication in the treatment of NeP and has been shown to be of benefit in RCTs for diabetic neuropathy and mixed NeP syndromes.¹⁸ It is a weak µ-opioid receptor agonist and weak SNRI.⁴³ The NeuPSIG also recommends it as a second-line agent.⁴² Tramadol might cause less constipation and nausea compared with other weak analgesics.⁴⁴ Along with common opioid side effects, tramadol can decrease seizure thresholds and can increase the risk of serotonin syndrome when combined with other serotonergic drugs.³¹

Opioids were found to be more effective than placebo for pain, with a moderate effect size, in a meta-analysis including 16 randomized trials for chronic NeP.⁴⁵ However, owing to their potential adverse effects, medical complications (endocrine dysfunction, sleep apnea, opioid-induced hyperalgesia), risks (overdose, diversion, addiction, withdrawal), and necessity of more specialized follow-up and monitoring, opioids are considered to be second-line agents for NeP (Table 3).⁴⁶ In the recent NeuPSIG systematic review and meta-analysis, opioids are recommended as third-line analgesics for the same reasons.⁴²

A meta-analysis of 62 RCTs found that the most common opioid-related adverse effects were nausea (28%), constipation (25%), drowsiness (24%), dizziness (18%), and vomiting (15%).⁴⁵ Although some tolerance to side effects develops, there is little tolerance to constipation in prolonged use. Long-term opioid use complications include opioid-induced hyperalgesia⁴⁷ and multiple endocrine axis suppression such as adrenal and gonadal suppression.⁴⁸ The 2017 Canadian Guideline for Opioids for Chronic Non-Cancer Pain is strongly recommended as a resource for family physicians.⁴⁶ An online and mobile resource, My Opioid Manager, is recommended to help inform and engage patients to work with their health care providers in managing their pain with opioids.⁴⁹ Another mobile app, Manage My Pain, has more than 25 000 active users and is used in chronic pain to empower the physician-patient relationship.⁵⁰

Third-line analgesics.

Cannabinoids have been moved from a fourth-line to a third-line treatment option for chronic NeP in the 2014 CPS NeP guidelines.⁷ The strongest evidence for cannabinoid use is for NeP from HIV, diabetic neuropathy, posttraumatic or postsurgical NeP, and mixed central and peripheral NeP states.^51–55 However, there is a paucity of high-quality studies with long trial duration, large sample size, and large effect size to better establish their efficacy and their potential for abuse. The NeuPSIG provides a weak recommendation against the use of cannabinoids in NeP owing to potential for misuse, diversion, and long-term risks in susceptible individuals.⁴² Side effects of cannabinoids can vary but usually include somnolence, “getting high,” confusion, dizziness, tachycardia, and hypotension.⁵⁶

Cannabinoid formulations in Canada currently consist of nabilone, nabiximols, and dried cannabis.⁵⁷ Dosing for dried cannabis is highly individualized and relies greatly on titration owing to complex pharmacology, interindividual genetic differences in cannabinoid receptors, metabolism, and previous exposure. In clinical trials with positive results using dried cannabis for NeP conditions, the delta-9-tetrahydrocannabinol dose per day did not exceed 125 mg, and maximum tetrahydrocannabinol by weight was 9.4%. Although there is no established dosing guideline for dried cannabis, the Health Canada monograph on cannabis provides “rough” dosing guidelines.⁵⁶ Dried cannabis is not approved or regulated by Health Canada because it has not gone through the necessary rigorous scientific trials for efficacy or safety. Provincial guides and policies on medical marijuana can be found on the Canadian Medical Protective Association website.⁵⁸ For family physicians starting, maintaining, or terminating dried cannabis prescriptions, preliminary guidelines have been created by the College of Family Physicians of Canada.⁵⁷

As per current guidelines, cannabis is not appropriate to start in those who are younger than 25 years of age, might be pregnant, have cardiovascular disease, have a respiratory disease, have a history of psychosis, or have a substance use disorder. In patients naïve to cannabis, a trial with a synthetic cannabinoid, usually nabilone, should be considered first. If dried cannabis is prescribed, physicians must continue to follow up and monitor patients to assess for potential misuse, abuse, and efficacy. Discontinuation of cannabis therapy is warranted when there is clearly no benefit or it is causing harm to the patient.⁵⁷ It is important also to be cognizant of cannabis hyperemesis syndrome as a differential diagnosis in young patients who present with cyclic vomiting and compulsive hot bathing.⁵⁹ There are several large-scale Canadian initiatives under way with the aim of creating evidence-based recommendations on the prescription of medical cannabis.

Fourth-line analgesics.

Selective serotonin reuptake inhibitors are another class of antidepressants that have some analgesic efficacy, with the exception of fluoxetine, in painful diabetic neuropathy and painful polyneuropathy.^60–63 Similar to SNRIs, there is a risk of serotonin syndrome with medications that increase serotonin levels and they are also contraindicated in combination with monoamine oxidase inhibitors.⁶⁴

Topical lidocaine is a local anesthetic useful in the management of peripheral NeP. It remains a second-line agent specifically for postherpetic neuralgia.¹⁸ However, there was no benefit shown in postsurgical nerve injury or in mixed NeP.^65,66 Topical lidocaine is safe, as only negligible levels are detected in blood and there are rarely any systemic side effects with topical use.⁶⁷

Capsaicin is another topical agent with evidence for effectiveness at high concentrations (8%) in postherpetic neuralgia and in painful HIV neuropathy for up to 12 weeks after a single application.⁶⁸ As initial application of capsaicin causes sensitivity of nociceptors leading to an intense burning sensation, local anesthetic before application might be required. In Canada, the high-potency capsaicin patch may be obtained through compassionate release.

Methadone is a synthetic opioid with unique N-methyl-d-aspartate and SNRI properties.⁶⁹ Only small RCTs and surveys have suggested efficacy in mixed NeP conditions.^70–72 In Canada, a specialized methadone exemption is required for prescribing and guidelines are available for its management in chronic pain.⁷³

Tapentadol is a newer opioid available in Canada with analgesic effect through µ-receptors and monoamine reuptake inhibition, but minimal effect on serotonin reuptake. This dual analgesic effect might contribute to its efficacy in treating painful diabetic neuropathy.⁷⁴ Like other opioids, common side effects include nausea and vomiting, somnolence, and dizziness but with lower incidence compared with oxycodone. Another advantage is the lower potential for metabolic variation due to enzyme polymorphism. Similar to tramadol, serotonin syndrome can occur when combined with other serotonergic drugs but at a reduced rate.⁷⁵ As the efficacy of tapentadol has only been studied in a single NeP pain model, it is considered a fourth-line agent and is not included as a second-line treatment with tramadol and other opioids.

Other anticonvulsants studied in NeP management include lamotrigine, lacosamide, topiramate, and valproic acid. Lamotrigine provided negative results in studies of diabetic neuropathy, mixed NeP, chemotherapy-induced NeP, and spinal cord injury pain. Results of small studies investigating lamotrigine’s effect in HIV neuropathy, trigeminal neuralgia, and central poststroke pain were positive.⁷⁶ Lacosamide has been mostly studied in the context of painful diabetic neuropathy with modest benefit.⁷⁷ Topiramate and valproic acid have had mixed results in NeP trials.¹⁸

Botulinum toxin injections represent a novel treatment in NeP with positive results in diabetic neuropathy and focal painful neuropathy. However, these studies are underpowered, with small sample sizes.^78,79 Therefore, the evidence for botulinum toxin remains preliminary and further evidence is needed.

Combination pharmacotherapy.

Recent review of combination pharmacotherapy in the treatment of NeP has involved variations of an opioid with gabapentin, pregabalin, or a TCA, the combination of gabapentin and nortriptyline, and various topical medications.⁸⁰ A meta-analysis of the combination of gabapentin with an opioid showed superiority in terms of analgesia when compared with gabapentin alone, but the combination also led to more discontinuations owing to side effects.⁸⁰ An RCT comparing duloxetine (60 mg daily) and pregabalin (300 mg daily) to high-dose duloxetine or pregabalin monotherapy did not yield any difference in 24-hour pain; however, all secondary outcome measures favoured combination therapy.⁸¹ Current evidence does not support a recommendation of any one specific drug combination for NeP, but it remains an important and understudied strategy.