Neuropathic and Anti-neuropathic agents

The International Association for the Study of Pain (IASP) defines neuropathic pain (NP) as pain "...initiated or caused by a primary lesion or dysfunction in the nervous system".

The management of patients with chronic NP is complex and response to existing treatments is often inadequate.

Approriate diagnosis and assessment are critcal to the successful treatment of NP. The diagnosis of NP can often be challeneging, the diagnostic criteria are evolviong, and NP commonly co-exists with other types of pain (e.g. low back pain associated with both radiculopathy and musculoskeletal abnormalities).

The assessment of NP should focus on:

Identifying and treating the underlying disease processes and peripheral or central nervous system lesions
Response to prior therapies
co-morbid conditions that can be affected by therapy

Particular attention should be paid to identifying co-existing depression, anxiety, sleep disterbances and other adverse impacts of NP on health-related quality of life, and both pain and its adverse effects should be reassessed frequently.

Patient education and support are critical components of the successful management of NP.

Patient and provider expectations regarding treatment effectivness and tolerability must be discussed, and realistic treatment goals should be established with the patient/s

Non-pharmacological methods of coping with pain should be discussed, including the importance of stress reduction, good sleep hygine, physical therapy and other potential useful interventions.

First Line Medications

Stepwise pharmalocgic management of neuropathic pain

Step 1 Initiate therpay of the disease causing NP, if applicable. Initiate symptom treatment with one or more of the following:

Nortriptyline Tricyclic Antidepressant (TCAs) and Selective Seritonin and Norepinephrine Reuptake Inhibitors (SSNRIs). Systematic reviews have consistentaly concluded that placebo-controlled trials have provided support for the efficacy of TCAs in the treatment of patients with NP, especially PHN and DPN. A substantial percentage of patients do not respond favourably to treatments with TCAs, as is also true of the other medications recommended for the treatment of NP, with no more than 40-60% of patients obtaining partial relief of their pain. TCAs have not differed significantly from placebo in RCTs of patients with HIV neuropathy, spinal cord injury, cisplatin neuropathy, neuropathic cancer pain, phantom limb pain, and chronic lumbar root pain.

Secondary amine TCAs (Nortiptyline and Desipramine) are preferred because they are better tolerated than tertiary amine TCAs (Amitriptyline and Imipramine) but have comparable analgesic efficacy. Amytriptyline in particular should be avoided in elderly patients. Vanlafaxine is an SSRI that inhibits seritonin reuptake at lower dosages and both seritonin and noradrenaline reuptake at higher dosages. RCTs in patients with painful DPN and painful polyneuropathies of various types (including DPN) demonstrated efficiay at dosages of 150-225 mg/day. RCTs in other populations, including those with post-mastectomy pain, various peripheral and central NP conditions, and PHN, demonstrated inconsistent or negative results.

Gabapentin or Pregabalin (calcium channel a2-d ligand) - both bind to the a2-d sub-unit of voltage gated calcium channels, decreasing the release of glutimate, noradrenaline, and substance P.

Pain reduction has been greater with Gabapentin than with placebo in RCTs of PHN, painful DPN, phantom limb pain, diverse peripheral NP conditions, Guillain-Barre` syndrome, neuropathic cancer pain, and acute and chronic spinal cord injury pain. In some RCTs, treatment with Gabapentin was also associated with improvements in sleep and various components of mood and health-related quality of life. Negative trials of Gabapentin include an unpublished study in painful DPN and recent studies of Compelx Regional Pain Syndrom (CRPS), type painful HIV neuropathy, chronic phantom limb and residual limb pain, and chemotherapy-induced neuropathy. Gabapentin is generally safe, has no clinically important drug interactions, and is available in generic forms. The main dose-limiting side effects are somnolence and dizziness (which are reduced by the gradual dosage titration) and peripheral oedema. In some patients, particulalrly the elderly, Gabapentin can cause or exacebate cognitive or gait impairment. Several weeks can be required to reach an effective dosage, which is usually between 1800 and 3600 mg/day (administered in three divided doses, increasing the night-time dose preferentally). Dosage reduction is necessary in patients with renal insufficiency. The onset of activity can be seen as early as the second week of therapy when titration is rapid, but peak effect usually occurs approximatly two weeks after a theraputic dose is achieved. Therefore, an adequate trial may require two or more months.

Pregabalin produces dose-dependant side effects simialr to those of Gabapentin. It also has demonstrated anxiolytic effects in RCTs of Generalised Anxiety Disorder, which may provide additional benifit for patients with chronic pain. A starting dose of 75mg at bedtime is used by some clinicians to reduce the likelihood of early side effects in elderly patients and in others especially prone to side effects.

For patients with localised peripheral NP - topical lignocaine used alone or in combination with one of the other first-line therpaies

As a topical preparation, it is recommended for patients with localised peripheral NP but not for patients with central NP
When used as recommended, the only side effects that occur with lignocaine are mild skin reactions (e.g. erythema and localised rash).
Because of its safety and ease of use, lignocaine gel can also be considered

For patients with acute neuropathic pain - neuropathic cancer pain or episodic exacerbations of severe pain, and when prompt pain relief during titration of a first-line medication to an efficacious dosage is required, opioid analgesics or tramadol may be used alone or in combination with one of the first-line therapies.

Step 2 Reassess pain and health related quality of life frequently

If substantial pain relief and tolerable side effects, continue treatment
if partial pain relief after an adequate trial, add one of the other first line medications
If no or inadequate pain relief at the target dosage after an adequate trial, switch to an alternative first-line medication

Step 3 If trials of first-line medications alone and incombination fail, consider second- and third-line medications or referral to a pain specialist or Multidisciplinary Pain Centre

Second-Line Medications That Can Be Used for First-Line Treatment in Selected Clinical Circumstances

Opioid analgesics and Tramadol have demonstrated efficacy in multiple RCTs in patients with NP, and when patients do not have a satisfactory response to the first-line medications alone or in combination with the first-line medications.

Opioid Analgesics

Oral opioid analgesics have demonstraed efficay in RCTs ranging from eight (8) days to eight (8) weeks in duration in patients with a variety of peripheral and central NP conditions, including painful DPN, PHN and phantom limb pain. However, morphine was not found to differ from placebo in a recent RCT for chronic nerve root pain.

Although opiod analgesics have demonstrated efficay in multiple RCTs in patients with NP, they are generally considered a second-line treatment for several reasons:

In head-to-head comparisons, opioids have have produced side effects more frequently than TCAs and Gabapentin, and some of the side effects can persist throughout long-term treatment.
The long-term safety of opioid treatment has not been systematically studied and, evidence that long-term opioid use is associated with the development of immunologic changes and hypogonadism , suggests that clinicians should not be guided by the assumption that safety is intrinsically better for opiods than other medications.
Experimental data suggest that opioid treatment can be associated with hyperalgesia; like tolerance, opioid-induced hyperanlgesia could potentially alter the risk-benifit ratio of long-term therapy in patients with various types of acute and chronic pain.

Third-line Medications (Anti-epiletic medications)

In contrast to its established efficacy to trigeminal neuralgia, Carbamazepine has yielded inconsistent results in RCTs of other types of neuropathic pain. These studies generally had limited methodological quality. Three positive trials of valproic acid in painful DPN or PHN were reported from a single centre, but an RCT conducted in patients with painful neuropathies by a different research group was negative.

Conclusion

TCAs, SSNRIs, Cacium channel a2-d ligands, and topical lignocain have demonstraed efficacy in NP and are recommended as first-line medications. In patients who have failed to respond to these first-line medications alone and in combination, opioid analgesics or Tramadol can be used as a second-line treatment alone or in combination with one of the first-line medications. Opioid analgesics and Tramadol can also be considered for first-line use in select clinical circumstances.

Ref: Pain 132 237-251