The end of a painful compromise?

My father gritted his teeth in agony and turned down further pain relief; it was then realised most of modern medicine is a compromise between two opposing factors: benefits versus costs.

In my fathers case it was a fight between achieving enough pain relief through morphine while still being conscious enough to comfort his children on what would soon become his death bed. This is common a problem in pain management, even in non-terminal illnesses.

Often sufferers of neuropathic pain are prescribed non-steroidal anti-inflammatory drugs (NSAIDs); taken at sub-maximal therapeutic doses because the side effects at a fully effective dose invariably lead to side-effects such as peptic ulcers⁽¹⁾ and a largely increased chance of heart problems⁽²⁾. Thankfully the field of pain management is one area now, where thanks to recent discoveries, the long-lasting battle between costs and benefits may be won by a small molecule known as BZP⁽³⁾.

It is clear that any analgesic with much greater specificity to mechanisms of nociception compared to other bodily functions would have minimal side-effects and revolutionise the treatment of pain; enabling suffers to abolish most of their suffering without having to endure other problems as a result.

And in 2006 a ground-breaking study revealed a way this may be possible.

The study reported the existence of a several related individuals from northern Pakistan who carried a mutation causing them to have absolutely no experience of pain⁽⁴⁾. Each individual as a result of their condition had obvious injuries; all had chewed off parts of their lips/tongue in youth without realising a problem, several had bone infections following breaking a leg and then continuing to walk around on the shattered limb – lacking the instinctive behaviour to rest it.

Arguably one of the most interesting things about these individuals is that apart from a complete lack of ability to feel pain they were completely healthy and correctly functioning. This sparked the research into answering the obvious question: can the state of these individuals be temporarily replicated in other people requiring pain relief?

It transpired that the individuals had a loss of function mutation in the SCN9A gene, coding for the alpha subunit specific to the Nav1.7 channel; apparently only located in the unmyelinated C-fibres of the dorsal root ganglia – the fibres which of course are responsible for transmitting information from painful stimuli.

This ground-breaking information led researchers to search for a compound capable of blocking this channel in order to answer the aforementioned question. As Na channels are responsible for production and propagation of most electrical activity throughout the body (importantly the heart and the brain), any blocker of these channels must be highly specific to be free of dangerous side-effects.

The compound BZP achieves this specificity and has been shown to be effective at reversing hyperalgesia in an animal model of inflammatory pain, equal to the NSAID rofecoxib; yet at a dose that induced no CNS deficits⁽³⁾. The compound was also shown to be efficacious at reducing allodynia in a model of neuropathic pain to a greater extent than typical analgesics used to treat this.

These promising results all occurred using concentrations lower than what’s required to cause observable side-effects.

Human studies will be required to fully establish whether these wonder-drugs truly are side-effect-free. But judging by the human mutation study and providing BZP is specific enough, it seems very likely that they will be. Thus, this drug has great potential at revolutionising the field of pain management by ending the battle once and for-all between the cost and benefits of treatment.

References:

1. Simone Rossi, ed (2006). Australian medicines handbook 2006.
2. Kearney, Pm; Baigent, C; Godwin, J; Halls, H; Emberson, Jr; Patrono, C. BMJ (Clinical research ed.) 332 (7553): 1302–8 (2006).
3. Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG. Nature; 444: 894–8 (2006)
4. McGowan, E., Hoyt,S.B., Li, X. H., Lyons, K. A & Abbadie, C. A. Anesthesia and Analgesia, 109, 951-958. (2009)