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Multimodal therapy in neuropathic pain: 2 is more than 1!

The famous Dutch surgeon Noordenbos wrote in 1959: "One-one synaptic transmission must be the exception rather than the rule in the nervous system. Any nerve cell located in the anterior horn. . . could hardly be expected to synapse at higher level with one such similar cell only. It will probably send ramifications to many other locations, and in turn be acted upon by the ramifications of many other cells. . . Far from being a continuous chain of short neurons, these fibres must constitute links in an extremely complicated nerve net in which, within limits, everything synapses more or less with everything else." It is clear that half a century later our therapy of pain is based on these deep insights of Noordenbos, and multimodal therapy is now the hallmark of how to treat neuropathic pain. This is because it is difficult to treat neuropathic pain with one drug only. In our centre we nearly always prescribe two or more oral drugs and mostly also topical creams and supplements together to get the patients out of the red zone of discomfort.

Giving more than 1 drug is already established for hypertension,[1] asthma,[2] and cancer.[3] For neuropathic pain prescribing more than one drug also makes sense.[4][5] Recently some studies were publised into the safety and efficacy of administrating several painkilleers together to treat neuropathic pain.

Gabapentin and nortriptylin for neuropathic pain

In a double blind study published in the Lancet this combination was evaluated in neuropathic pain due to diabetes and due to herpes zoster.[6] The maximum dose of gabapentin administered was 3600 mg and of nortriptylin 100 mg.

Step by step one increased the dose of both drugs. Various recommended scales were used.[7][8][9] The conclusion of the authors was:

…at maximum tolerated dose, pain was 3·2 (2·5 to 3·8) for gabapentin, 2·9 (2·4 to 3·4) for nortriptyline, and 2·3 (1·8 to 2·8) for combination treatment. Pain with combination treatment was signifi cantly lower than with gabapentin (–0·9, 95% CI –1·4 to –0·3, p=0·001) or nortriptyline alone (–0·6, 95% CI –1·1 to –0·1, p=0·02).

Furthermore, the dose administered was lower in this combination therapy as compared to traditional mono-dosing:

 ….tolerated dose of gabapentin was 2433 mg as monotherapy versus 2180 mg in combination (p=0·0009). For nortriptyline, maximum tolerated dose was 61·6 mg as monotherapy versus 50·1 mg in combination (p=0·0006).

Gabapentin and morphine in neuropathic pain

In a comparable design gabapentine and morphine were combined.[10] The combination again was superior: at a maximal tolerated dose of the study drug was as follows: 5.72 at baseline, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination (P<0.05 for the combination vs. placebo, gabapentin, and morphine)

Gabapentin and oxycodone in neuropathic pain

In an other study in diabetes neuropathic pain patients the combination of gabapentin and oxycodone was evaluated.[11] Here the results were also in favor of the combination treatment:

The overall treatment effect was greater with oxycodone-gabapentin than with placebo-gabapentin (P = 0.007). Oxycodone-gabapentin also significantly improved pain relief vs gabapentin alone (P = 0.003). Oxycodone-gabapentin co-administration was associated with less escape medication use (P = 0.03) and fewer nights of disturbed sleep (P < 0.05). Discontinuations due to lack of therapeutic effect were much lower (14% vs 54%) with oxycodone-gabapentin. The commonly seen opiate-induced adverse events were not exacerbated by the combination of oxycodone and gabapentin.

Interaction problems need to be adressed

Interactions are always possible, but we can find many sources easy to access to find out the potential interactions when administrating several drugs together. Furthermore, always consult with the pharmacist.

From the Centre for the study and treatment of neuropathic pain and neuropathy in Soest, the Nertherlands

This site helps patients and treating physicians, neurologists, anesthesiologists and other pain specialists to find the best and most up to date research findings related to neuropathy and neuropathic pain and the treatment thereof.

In our centre we are specialised in treating patients suffering from neuropathic pain and neuropathy following an Integrated Medicine concept. Part of our activities are within the field of consultation. We assist pharmaceutical companies in R&D strategies related to finding new drugs to treat neuropathic pain and neuropathy.

February 2010, Jan M. Keppel Hesselink, MD, PhD. David J. Kopsky, MD

Bron: Noordenbos, Willem. Pain: Problems Pertaining to the Transmission of Nerve Impulses Which Give Rise to Pain. Amsterdam: Elsevier, 1959 



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