Tackling Nerve Pain

Motivation: Pain is the bane of internists - particularly neuropathic pain. The gnawing, burning pain keeps people (patients and internists) up all night debating whether to use IV opioids.  And, gabapentin hardly seems up to the job.  There were several instances last year when even mega-doses of gabapentin failed to lessen the pain.  I often wondered at that point, what next?  To start a new agent, should I stop gabapentin? (And, is this pain real?)

During a clinic this year, one of the attendings pointed out a helpful trial that attempted to deal with failed control of neuropathic pain.  The trial tested combination of tricylcic agent nortriptyline with gabapentin.  As way of background, gabapentin is an alkylated analogue of GABA that is actually thought to work through modulating calcium channel subunits.  Nortriptyline is derived from amitriptyline with multiple effects including blockade of norepinephrine and serotonin re-uptake, blockade of sodium channels, anti-cholinergic actions, and antagonism of NMDA receptors.

Paper: Gilron, I., Bailey, J.M., Tu, D. et. al. "Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial" Lancet (2009); 374: 1252.

Methods: Double-blind crossover trial in patients with diabetic polyneuropathy and postherpetic neuralgia with persistent neuropathic pain. Randomized trial of three treatments - gabapentin, nortriptyline, and combined gabapentin and nortriptyline.  In crossover design, each of three groups spent 6 weeks in each of the three treatment groups (received placebo pill for second agent when getting just gabapentin or nortriptyline).  After 6 weeks, each of the groups were switched to one of the other three treatment assignements.  During the trial period, drug doses were titrated to maximum tolerated dose.  Primary outcome was mean daily pain (0-10 rating scale).

Results:
Subjects: The trial enrolled total of 56 participants.  Of these patients, 40 had diabetic polyneuropathy and 16 had post-herpetic neuralgia.  All of the patients were white with men comprising 65% of diabetic groups and 56% of post-herpetic neuralgia group.  In the diabetic group, 20% were taking opioids with about 33% having been exposed to prior tricyclic and 20% having been exposed to gabapentin/pregabalin.  Similarly, in the post-herpetic neuralgia group, 25% were taking opioids with about 31% having been exposed to prior tricyclic and 44% having been exposed to gabapentin/pregabalin.

Gabapentin vs. Nortriptyline: As monotherapy, both gabapentin and nortriptyline achieved lower daily pain intensity compared to baseline (5.4 in baseline vs. 3.2 for gabapentin; 5.4 vs. 2.9 for nortriptyline). The pain rating is significantly lower from baseline but is not significantly different between drugs.  Similarly, neither drug was superior to each other in terms of worst pain in 24 hours, least pain in 24 hours, or percentage pain relief on treatment.

Combination Therapy: Combined nortriptyline and gabapentin was significantly superior to gabapentin and nortriptyline monotherapy in terms of daily pain intensity (2.3 in combination vs 3.2 for gabapentin alone, p=0.001; 2.3 vs 2.9 for nortriptyline, p=0.02).  Combination therapy also provided better percentage pain relief on treatment (63.4% vs. 48.1% for gabapentin, p=0.007; vs. 45.7% for nortriptyline, p=0.002).  In secondary analysis, Beck depression score was significantly better for combination therapy compared to nortriptyline (5.4 vs. 6.8 for nortriptyline, p=0.01).  Self-reprorted vitality was also higher with gabapentin and combination therapy compared to nortriptyline alone. Depression scores were not different between combination therapy and gabapentin.

Dosage: As monotherapy, average maximum doses of gabapentin was 2433 mg/day while that of nortriptyline was 61.6 mg/day.  In combination, average gabapentin dose was 2180 mg/day and nortriptyline dose was 50.1 mg/day.

Adverse Effects: No serious side effects were noted.  Dry mouth was more frequent with nortriptyline while inability to concentrate was more frequent with gabapentin.

Discussion: For patients with poorly controlled neuropathic pain, combination therapy with nortriptyline and gabapentin was superior to monotherapy.  While both drugs appeared to be equivalent in terms of controlling pain, I was surprised at the worse depression scores and decreased vitality with nortriptyline monotherapy compared to gabapentin.  Given the alternate use as anti-depressant, I would have expected nortriptyline to be at least as good as gabapentin in terms of mood.  This analysis is, of course, secondary and limited by the small number of subjects (56 total patients), but given the limited data, I would start with gabapentin monotherapy and then add nortriptyline as an adjunctive agent.  Another cautionary note is that the tolerated doses of gabapentin in the trial was more than 2000 mg/day.  With the usual starting dose of 300 mg thrice daily, the drug needs to be significantly uptitrated prior to pronouncing therapeutic failure.