Summary
Knowledge of the anatomical and physiological mechanisms which are involved in the pain phenomenon is incomplete, but current opinion is moving away from the concept of pain as a specific sensory modality. Mechanical, thermal or electrical stimuli may cause pain, the ‘adequate stimulus’ usually implying tissue damage, although in certain conditions of neurological abnormality a normally innocuous stimulus may be painful.
Neurological factors: It is suggested that the function of ‘coding’ is performed peripherally by receptors which react to more than one type of stimulus but with preferential sensitivity, and more centrally by such phenomena as facilitation, inhibition and synchronisation. ‘Decoding’ may depend on such factors as gross temporal pattern, spatial summation and detailed anatomical connections. At central level many areas of the brain are concerned with pain, e.g. thalamus, limbic system, hypothalamus, brain stem reticular formation and parietal and frontal cortices, thus rendering the concept of a ‘pain centre’ untenable.
The Gate Control theory postulates that cells of the substantia gelatinosa function as a gate, which is opened or closed to incoming stimuli by impetus transmitted by small or large nerve fibres respectively, and that further afferent transmission of these impulses is modified by factors such as attention, emotion and past experience.
The major pharmacological effects of morphine in man are analgesia, respiratory depression, variable mental sedation, nausea and vomiting, and constipation. There is little effect on the cardiovascular system. In the relief of pain its actions are complex and include effects on both perception of the pain provoking stimulus and the affective response to it. Tolerance, physical dependence, and addiction occur readily with morphine, and are the greatest bar to the freer use of the drug.
There are many other drugs which are derivatives of, or pharmacologically similar to morphine. In general, these drugs share the same spectrum of activity, differing only in relatively minor aspects. All share the same serious side-effects of respiratory depression and addiction liability. The n-allyl derivatives of the opiates also have similar pharmacological actions to the parent compounds except that psychotomimetic subjective effects may occur, the addiction potential is much less and, if given with an opiate, they will reverse all the actions of the opiate. In opiate addicts, these drugs will provoke an acute withdrawal syndrome. One member of this series, pentazocine, is a weak antagonist but a relatively strong agonist. It is useful clinically as an analgesic.
The absorption of morphine and morphine-like drugs is generally good following parenteral administration, but poor and unpredictable after oral administration. The absorbed drug is largely taken up and concentrated in ‘non-target’ areas which act as a short term store for the opiate, releasing the drug as the plasma level falls. All opiates cross the placenta readily; with the possibility of higher levels in the fetal than in the maternal circulation. Biotransformation in the liver is the chief limiting process for opiate activity.
Pethidine and possibly all pharmacologically similar agents, are potentiated in patients who have received monoamine oxidase inhibitor drugs. The mechanism is uncertain but may be related to elevation of the cerebral content of 5-hydroxytryptamine.
The specific opiate antagonists nalorphine, levallorphan and naloxine reverse the clinically important actions of the agonists and have their principal application in the treatment of absolute or relative overdose. There appears to be little indication for the use of opiate-antagonist mixtures. Of the non-specific antagonists which have been advocated for the alleviation of a particular side-effect, only cyclizine appears to have proven clinical value.
From a clinical viewpoint pain can be regarded as the product of an initial stimulus modified by factors such as personality, age, sex, past experience, social status and, most important, the significance which the pain assumes for the patient. This pain-significance factor is of great relevance in the assessment of analgesic drugs as it is difficult to simulate in the laboratory, thus pain produced experimentally may fail to evaluate some of the more important analgesic mechanisms of the strong analgesics, namely the relief of anxiety and elevation of mood.
Clinically, the strong analgesics are widely used in their relief of severe pain. The particular problems presented by their use in childbirth, myocardial infarction, postoperative pain and trauma are discussed, along with the more difficult problem of chronic severe pain.
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Loan, W.B., Morrison, J.D. Strong Analgesics: Pharmacological and Therapeutic Aspects. Drugs 5, 108–143 (1973). https://doi.org/10.2165/00003495-197305020-00002
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DOI: https://doi.org/10.2165/00003495-197305020-00002