An Update on Analgesics

From British Journal of Anaesthesia

I. Power

Posted: 08/03/2011; Br J Anaesth. 2011;107(1):19-24. © 2011

 

• Abstract and Introduction
• New Opioid Formulations
• Methadone
• Paracetamol
• Tapentadol
• Dual Oxcarbazepine and COX Inhibitors
• Catecholamine-O-methyltransferase Polymorphisms
• Gabapentin
• Methylxanthines
• Ropivacaine and Neuropathic Pain
• Fentanyl
• Opioid Antagonists
• Naloxone and Oxycodone
• Opiorphin
• The Endocannabinoid System
• Ibudilast
• Antagonism of Opioid-induced Ventilatory Depression by Ampakines
• Conclusion

• References
• Sidebar

Abstract

Recent introduction of new analgesics into the clinic is best described as a slow process with activity classified into two main areas: improving analgesic efficacy/potency and reducing side-effect profile. This review article describes some of the recent advances with an emphasis on use in the acute setting.
In this respect, opioids continue to be the mainstay (but not the only) analgesic and there have been important improvements in their clinical effect profile. For example, tapentadol has been introduced as a mixed opioid and norepinephrine uptake inhibitor which, unlike tramadol, does not require metabolic activation and does not suffer from isomer-dependent pharmacodynamics.
Opioid antagonists have received much attention recently either used alone, methylnaltrexone (s.c) or alvimopan (p.o), or in combination, Targinact (oxycodone/naloxone), and appear to be effective in reducing opioid side-effects such as those in the gastrointestinal tract. Other agents where there has been recent development include the use of gabapentin, methylxanthines, and local anaesthetics. An interesting area of translation of basic research is in the inhibition of breakdown of endogenous opioids with opiorphin, targeting of the endocannabinoid system, and the use of ampakines to obtund opioid-induced side-effects. It is clear that there is still much work to be done, but the need for highly efficacious analgesics with good side-effect profile remains.

Introduction

This article was written as part of Professor Jennifer Hunter's Festschrift entitled 'Anaesthesia and Critical Care in the 21st Century: The First Decade' which will be held in May 2011. I was asked to present an update on analgesics, mainly those used in the 'acute' setting that would give some idea of the advances we have made in alleviating pain after surgery or trauma. My consideration of this was rapidly fashioned by various articles published in the recent past, indicating that for the acute setting, progress in terms of the introduction of new drugs has been incredibly slow.
Woolf in an article about overcoming obstacles to developing new analgesics states that 'despite substantial financial investment by the pharmaceutical industry over several decades, there has been little progress in developing new efficacious and safe analgesics'. Woolf then indicates that this is leading some pharmaceutical companies to consider withdrawing from the acute pain relief market, and that the problem might be a lack of understanding of pain itself. Certainly, there does seem to be a lack of understanding of how to design studies to investigate acute pain relief. This is clearly shown by a recent article entitled 'Getting the pain you expect'.
The problem seems to be our design of studies in many ways, which allows us to accept placebos, 'nocebos' (that is, negative outcomes, see Tracey), and reappraisal effects in humans. Our clinical studies tend to neglect these and to set them aside and Quessyhas addressed this issue in an article entitled 'Where are the new analgesics?' and suggests an alternative approach to early phase analgesic trials using a multivariate input model. Certainly, trial design does seem to be a large part of the problem, but also the issue is that in addressing pain, we must also address safety and efficacy. This was very well demonstrated by the attempts to improve upon the safety profile of non-steroidal anti-inflammatory drugs where by selectively changing the action of drug molecules, the enzyme affected was influenced. The result was that efficacy was improved, but safety markedly affected, so that some of the drugs were withdrawn because of unexpected cardiovascular side-effects.
As a result, senior researchers are now asking the question 'what is this thing called pain?'There is no doubt that when we deal with pain after surgery or trauma, we are dealing with the various classifications proposed by Woolf which include nociceptive: associated with the detection of potentially tissue damaging stimuli; inflammatory: tissue damage; and pathological: damage to the nervous system (neuropathic).
Part of the problem with pain after surgery is that consent renders the patient open to accepting nociceptive damage and anaesthesia, while greatly minimizing and allowing invasive surgery has very little effect on the nociceptive process. Also, after surgery and trauma, these classifications become somewhat blurred as neuropathic pain can appear immediately after a surgical process. In looking for new analgesics that work in the acute setting, there is a problem of having to address many types of pain simultaneously, using the same compounds. We are indeed a long way from Tracey's postulation of making postoperative pain 'pleasant'.
However, Tracey's idea of arranging more suitable studies may well render an individualized approach to the problem of pain possible and produce safer and more effective analgesics.

Analgesia for acute pain relief still tends to be drawn from the traditional opiates, aspirin and the non-steroidal drugs, paracetamol, and local anaesthetics.
The opiates were in wide use as a natural product, and, for example, in the 15th century, 'the Soporific sponge' was mentioned where opium is mixed with various herbal products and then dried, so that the sponge could be warmed later and used for pain relief. 'Opium' was used widely in the 19th century and indeed quoted in the family doctor as 'the best medicine we possess'. In 1803, Serturner assimilated crystals from opium and named them 'morphine' after the Greek God of dreams, Morpheus. Morphine was delivered on the point of a lancet and washed into the wound, injections not yet being available. This moved on until Stein and colleaguesrealized that opioids were part of the physiology of the inflammatory, painful process and suggested that where tissue damage occurred, local anti-inflammatory analgesic opioids were released to aid the repair process.
Opioids have continued to be the mainstay of our armamentarium against pain based on new formulations, mixed preparations, novel norepinephrine inhibitors, and the use of opioid antagonists to address the thorny issue of opioid-related gut side-effects. Each of the evidence-based guidelines that exist about the relief of acute pain address the efficacy and safety in different ways, but the aim has been to improve on the efficacy of drugs like morphine and reduce its drastic side-effects, including nausea, gastrointestinal effects, and acute loss of the patent airway and hence hypoxia. Aspirin was introduced as an attempt to improve upon the palatability profile of the older sodium salicylate and the non-steroidals resulted from that in due time. Paracetamol was made available by an entirely different chemical process, but this routine drug taken by all of us seems to be one of the best analgesics that work from cradle to grave, although smitten by the dire side-effect of liver impairment upon overdose. New drugs such as tramadol and now tapentadol make use of the endogenous pain-modulating pathway that occurs in response to tissue damage, giving the pharmacological site of action for most of our presently used drugs.Opioids work at various sites of the pain pathway but are of course inherent to the modulation of pain physiologically. Non-steroidal anti-inflammatory drugs work at the site of tissue damage and in the central nervous system. The descending pathways from the brain down to the lower sensory pathways for pain depend on various substances, including enkephalins, endorphins, and norepinephrine that have been used for the production of analgesics. The introduction of tapentadol is an example of this. Therefore, attempts need to be made to improve efficacy and reduce side-effects in an individualized fashion. It may be that increased understanding of the genetic role of our pain physiology might allow us to do this and produce individualized approaches to tissue damage and pain, but again we are someway from that at present. One new possibility is the introduction of 'epigenetics in pain and analgesia', which might allow a personalized, individualized approach to pain and tissue damage.
The aim should be to stop viewing morphine, for example, as a two-faced God, Janus, that produces powerful analgesia that is blighted by common, serious, and sometimes life-threatening adverse effects.

for rest of article refer: 
http://www.medscape.com/viewarticle/745129?src=mp&spon=17