Annual Scientific Meeting, Belfast; November 2000.

NEW ANALGESICS

Professor David J Rowbotham

The Melzack and Wall gate-control theory of pain had a fundamental effect on our understanding of pain mechanisms. It is well known that this theory offers an explanation for the mechanism of action of TENS, spinal cord stimulation and psychological methods for pain management. Perhaps more importantly, this theory stimulated basic scientists to identify the receptors and neurotransmitters involved in the modulation of pain pathways in the CNS, and the spinal cord. This basic research is now bearing fruit with respect to the availability for human administration of new analgesics with novel modes of action.

The cholecystokinin receptor system (CCK_A, CCK_B) is known to be upregulated in pain states and antagonises opioid receptor stimulation (1). Relatively non-specific antagonist have shown some promise in pain states (2). Specific antagonists are now available and early experience with these novel compounds is promising. Some analgesic activity of adenosine type-1-agonists has been identified in humans (3) and these compounds may have a role in pain management.

Presently, there is considerable interest in the potential use of cannabis for pain. Cannabinoids are involved in the modulation of pain pathways in the CNS and in the peripheral inflammatory response (4). We have recently completed a double-blind placebo-controlled study of the effect of d -9-tetrahydrocannabinol (main active constituent of cannabis) for postoperative pain and the results of this study will be reviewed.

Other receptor systems involved in pain transmission are currently under investigation, these include glutamate (5), glycine (6) and the galanin (7) receptors.

Opioids have inhibitory effects on pain pathways in the CNS, particularly in the spinal cord. Since the 1970s, considerable advances in our understanding of the mu, kappa and delta opioid receptor have been made. However, the search for clinically useful drugs active at subtypes of these receptors has been relatively fruitless. The recent discovery of the "orphan" (ORL-1) receptor may have practical significance as this receptor is active in pain pathways. It is involved in many other physiological systems but it is not associated with respiratory depression, nausea and vomiting and addictive behaviour (8). Agents acting at this receptor are currently under investigation in man.

Acute pain is generated by the peripheral response to injury and many compounds are involved in this, including prostaglandins, bradykinin, TrK receptors, VIP, cytokines, substance P, calcitonin G-related protein and cannabinoids. COX 2 specific NSAIDs represent a considerable advance with respect to safety and side-effects, especially gastric ulceration and platelet function (9-11). However, it is not yet clear whether they offer any advantages with respect to renal function. Data describing a new water soluble COX 2 specific agent which is being developed specifically for acute pain will be described (12). The EP1 receptor is implicated in the algesic actions of prostaglandins (13) and it may be that drugs acting at specific prostaglandin receptors will be effective analgesics with few side-effects.

Ion channels are a potential site of action for analgesic drugs, particularly in neuropathic pain states. It is now clear that there are numerous subtypes of these channels and agents aimed at inhibiting channels involved specifically in pain pathways are under investigation.

References

1. WiesenfeldHallin Z, Xu XJ. The role of cholecystokinin in nociception, neuropathic pain and opiate tolerance. Regulatory Peptides 1996;65:23-28.

2. McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic: Efficacy of morphine in humans with chronic benign pain. Anesthesia and Analgesia 1998;87:1117-1120.

3. Sjolund KF, Segerdahl M, Sollevi A. Adenosine reduces secondary hyperalgesia in two human models of cutaneous inflammatory pain. Anesthesia and Analgesia 1999;88:605-610.

4. Hirst RA, Lambert DG, Notcutt WG. Pharmacology and potential therapeutic uses of cannabis. British Journal of Anaesthesia 1998;81:77-84.

5. Hudspith MJ. Glutamate: A role in normal brain function, anaesthesia, analgesia and CNS injury. British Journal of Anaesthesia 1997;78:731-747.

6. Christensen D, Gautron M, Guilbaud G, Kayser V. Combined systemic administration of the glycine/NMDA receptor antagonist, (+)-HA966 and morphine attenuates pain-related behaviour in a rat model of trigeminal neuropathic pain. Pain 1999;83:433-440.

7. Ahmad S, O'Donnell D, Payza K, Ducharme J, Menard D, Brown W, Schmidt R, Wahlestedt C, Shen SH, Walker P. Cloning and evaluation of the role of rat GALR-2, a novel subtype of galanin receptor, in the control of pain perception. Galanin: Basic Research Discoveries and Therapeutic Implications: Annals of the New York Academy of Sciences, 1998:108-119.

8. Darland T, Heinricher MM, Grandy DK. Orphanin FQ/nociceptin: a role in pain and analgesia, but so much more. Trends in Neurosciences 1998;21:215-221.

9. Clemett D, Goa KL. Celecoxib - A review of its use in osteoarthritis, rheumatoid arthritis and acute pain. Drugs 2000;59:957-980.

10. Emery P, Zeidler H, Kvien TK, Guslandi M, Naudin R, Stead H, Verburg KM, Isakson PC, Hubbard RC, Geis GS. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999;354:2106-2111.

11. Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: A randomized, controlled trial. Journal of Clinical Pharmacology 2000;40:124-132.

12. Cannon GW. Rofecoxib: A specific cyclooxygenase inhibitor. Drugs of Today 2000;36:255-262.

13. Bley KR, Hunter JC, Eglen RM, Smith JM. The role of IP prostanoid receptors in inflammatory pain. Trends in Pharmacological Sciences 1998;19:141-147.

14. Martin BR, Lichtman AH. Cannabinoid transmission and pain perception. Neurobiology Of Disease 1998;5:447-461.