provides an algorithm for the pharmacological management of NeP, and provides dosing guidelines for selected agents. Nonpharmacological interventions, including physiotherapy, exercise programs and psychological treatment modalities, are also important to improve outcomes.
Figure 1) Stepwise pharmacological management of neuropathic pain. *5% gel or cream – useful for focal neuropathy such as postherpetic neuralgia (the lidocaine patch is not available in Canada); †Cannabinoids, methadone, lamotrigine, topiramate, (more ...)
Dosing regimens for selected agents for neuropathic pain
TCAs, gabapentin and pregabalin are all considered first-line agents in the management of chronic NeP. It is reasonable to initiate treatment with either a TCA or an anticonvulsant such as gabapentin or pregabalin. Secondary amine TCAs (nortriptyline and desipramine) are better tolerated than tertiary amine TCAs (amitriptyline and imipramine) and have comparable analgesic efficacy. Amitriptyline, because of its tendency to produce sedation, constipation and urinary retention, should generally be avoided in elderly patients. All antidepressants take approximately two weeks to exert their full analgesic effect at any particular dose, and this needs to be communicated to patients to optimize compliance.
Gabapentin and pregabalin appear similar in terms of their mechanisms of action, efficacies and side-effect profiles, and allow for more rapid titration than antidepressant agents. Pregabalin carries the advantage of twice daily dosing and linear pharmokinetics relative to gabapentin.
If a TCA fails, switch to an anticonvulsant or vice versa. If a TCA provides only partial pain relief, add an anticonvulsant. The SNRIs are considered to be second line to TCAs because the latter agents provide more robust evidence of efficacy and are much less expensive. However, the TCAs have a more challenging side effect profile and are relatively contraindicated in patients with significant cardiovascular disease (17
Topical lidocaine is a good second-line analgesic for an elderly patient with a focal painful neuropathy like postherpetic neuralgia because side effects are usually negligible.
When first-line and second-line medications have failed, tramadol or a conventional opioid analgesic may be useful as third-line treatment. It is reasonable to consider a short-acting opioid such as oxycodone with acetaminophen (Percocet, Bristol-Myers Squibb Canada) for breakthrough pain during titration of first-line and second-line agents, if needed. If there is an inadequate response, the total daily dose of the short-acting opioid may provide guidance as to the initial maintenance dose of a controlled-release opioid analgesic. Intractable pain may require treatment with the combination of an antidepressant, an anticonvulsant and an opioid analgesic. Support for combination pharmacotherapy comes from a recent study reporting enhanced analgesia with a morphine-gabapentin combination relative to either drug alone (61
Although opioid analgesics have a NNT comparable to that of TCAs and perhaps better NNT than anticonvulsants, there are several reasons for their relegation to third-line analgesics for the management of NeP. Although tolerance often occurs to sedation, nausea and vomiting (and these latter side effects can be treated with antiemetics), there is very little tolerance to constipation and almost all patients placed on long-term opioid analgesics require a bowel regimen with continued monitoring of bowel function. In addition, periodic monitoring of risk of substance abuse and careful documentation of opioid prescriptions should be undertaken. Canadian guidelines for the use of opioid analgesics for the treatment of chronic noncancer pain are available (62
Fourth-line agents for the management of NeP include cannabinoids, methadone and anticonvulsants with lesser evidence of efficacy such as lamotrigine, topiramate and valproic acid. These should be considered when other options have failed or are not possible. They may be considered adjunctive therapies if there are no concerns regarding polypharmacy or drug interactions.