Source of opioids. Morphine is an opium alkaloid (p. 4). Besides morphine, opium contains alkaloids devoid of analgesic activity, e.g., the spasmolytic pa-paverine, that are also classified as opium alkaloids. All semisynthetic derivatives (hydromorphone) and fully synthetic derivatives (pentazocine, pethidine = meperidine, l-methadone, and fentanyl) are collectively referred to as opioids. The high analgesic effectiveness of xenobiotic opioids derives from their affinity for receptors normally acted upon by endogenous opioids (enkepha-lins, p-endorphin, dynorphins; A). Opi-oid receptors occur in nerve cells. They are found in various brain regions and the spinal medulla, as well as in intramural nerve plexuses that regulate the motility of the alimentary and urogenital tracts. There are several types of opioid receptors, designated j, 8, k, that mediate the various opioid effects; all belong to the superfamily of G-protein-coupled receptors (p. 66).
Endogenous opioids are peptides that are cleaved from the precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. All contain the ami-no acid sequence of the pentapeptides [Met]- or [Leu]-enkephalin (A). The effects of the opioids can be abolished by antagonists (e.g., naloxone; A), with the exception of buprenorphine.
Mode of action of opioids. Most neurons react to opioids with hyperpo-larization, reflecting an increase in K+ conductance. Ca2+ influx into nerve terminals during excitation is decreased, leading to a decreased release of excitatory transmitters and decreased synap-tic activity (A). Depending on the cell population affected, this synaptic inhibition translates into a depressant or excitant effect (B).
Effects of opioids (B). The analgesic effect results from actions at the level of the spinal cord (inhibition of noci-ceptive impulse transmission) and the brain (attenuation of impulse spread, inhibition of pain perception). Attention and ability to concentrate are impaired. There is a mood change, the direction of which depends on the initial condition. Aside from the relief associated with the abatement of strong pain, there is a feeling of detachment (floating sensation) and sense of well-being (euphoria), particularly after intravenous injection and, hence, rapid buildup of drug levels in the brain. The desire to re-experience this state by renewed administration of drug may become overpowering: development of psychological dependence. The atttempt to quit repeated use of the drug results in withdrawal signs of both a physical (cardiovascular disturbances) and psychological (restlessness, anxiety, depression) nature. Opioids meet the criteria of "addictive" agents, namely, psychological and physiological dependence as well as a compulsion to increase the dose. For these reasons, prescription of opioids is subject to special rules (Controlled Substances Act, USA; Narcotic Control Act, Canada; etc). Regulations specify, among other things, maximum dosage (permissible single dose, daily maximal dose, maximal amount per single prescription). Prescriptions need to be issued on special forms the completion of which is rigorously monitored. Certain opioid analgesics, such as codeine and tramadol, may be prescribed in the usual manner, because of their lesser potential for abuse and development of dependence.
Differences between opioids regarding efficacy and potential for dependence probably reflect differing affinity and intrinsic activity profiles for the individual receptor subtypes. A given sustance does not necessarily behave as an agonist or antagonist at all receptor subtypes, but may act as an agonist at one subtype and as a partial agonist/antagonist or as a pure antagonist (p. 214) at another. The abuse potential is also determined by kinetic properties, because development of dependence is favored by rapid build-up of brain concentrations. With any of the high-efficacy opioid analgesics, overdosage is likely to result in respiratory paralysis (impaired sensitivity of medullary chemo-receptors to CO2). The maximally possible extent of respiratory depression is thought to be less in partial agonist/ antagonists at opioid receptors (pentaz-ocine, nalbuphine).
The cough-suppressant (antitussive) effect produced by inhibition of the cough reflex is independent of the effects on nociception or respiration (antitussives: codeine. noscapine).
Stimulation of chemoreceptors in the area postrema (p. 330) results in vomiting, particularly after first-time administration or in the ambulant patient. The emetic effect disappears with repeated use because a direct inhibition of the emetic center then predominates, which overrides the stimulation of area postrema chemoreceptors.
Peripheral effects concern the motility and tonus of gastrointestinal smooth muscle; segmentation is enhanced, but propulsive peristalsis is inhibited. The tonus of sphincter muscles is raised markedly. In this fashion, morphine elicits the picture of spastic constipation. The antidiarrheic effect is used therapeutically (loperamide, p. 178). Gastric emptying is delayed (py-loric spasm) and drainage of bile and pancreatic juice is impeded, because the sphincter of Oddi contracts. Likewise, bladder function is affected; specifically bladder emptying is impaired due to increased tone of the vesicular sphincter.
Uses: The endogenous opioids (metenkephalin, leuenkephalin, p-en-dorphin) cannot be used therapeutically because, due to their peptide nature, they are either rapidly degraded or excluded from passage through the blood-brain barrier, thus preventing access to their sites of action even after parenter-al administration (A).
Morphine can be given orally or parenterally, as well as epidurally or intrathecally in the spinal cord. The opi-oids heroin and fentanyl are highly lipo-philic, allowing rapid entry into the CNS. Because of its high potency, fenta-nyl is suitable for transdermal delivery (A).
In opiate abuse, "smack" ("junk," "jazz," "stuff," "China white;" mostly heroin) is self administered by injection ("mainlining") so as to avoid first-pass metabolism and to achieve a faster rise in brain concentration. Evidently, psychic effects ("kick," "buzz," "rush") are especially intense with this route of administration. The user may also resort to other more unusual routes: opium can be smoked, and heroin can be taken as snuff (B).
Metabolism (C). Like other opioids bearing a hydroxyl group, morphine is conjugated to glucuronic acid and eliminated renally. Glucuronidation of the OH-group at position 6, unlike that at position 3, does not affect affinity. The extent to which the 6-glucuronide contributes to the analgesic action remains uncertain at present. At any rate, the activity of this polar metabolite needs to be taken into account in renal insufficiency (lower dosage or longer dosing interval).
Tolerance. With repeated administration of opioids, their CNS effects can lose intensity (increased tolerance). In the course of therapy, progressively larger doses are needed to achieve the same degree of pain relief. Development of tolerance does not involve the peripheral effects, so that persistent constipation during prolonged use may force a discontinuation of analgesic therapy however urgently needed. Therefore, dietetic and pharmacological measures should be taken prophylacti-cally to prevent constipation, whenever prolonged administration of opioid drugs is indicated.
Morphine antagonists and partial agonists. The effects of opioids can be abolished by the antagonists naloxone or naltrexone (A), irrespective of the receptor type involved. Given by itself, neither has any effect in normal subjects; however, in opioid-dependent subjects, both precipitate acute withdrawal signs. Because of its rapid pre-systemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrex-one may be used as an adjunct in withdrawal therapy.
Buprenorphine behaves like a partial agonist/antagonist at j-receptors. Pentazocine is an antagonist at j-recep-tors and an agonist at K-receptors (A). Both are classified as "low-ceiling" opi-oids (B), because neither is capable of eliciting the maximal analgesic effect obtained with morphine or meperidine. The antagonist action of partial agonists may result in an initial decrease in effect of a full agonist during changeover to the latter. Intoxication with buprenor-phine cannot be reversed with antagonists, because the drug dissociates only very slowly from the opioid receptors and competitive occupancy of the receptors cannot be achieved as fast as the clinical situation demands.
Opioids in chronic pain: In the management of chronic pain, opioid plasma concentration must be kept continuously in the effective range, because a fall below the critical level would cause the patient to experience pain. Fear of this situation would prompt intake of higher doses than necessary. Strictly speaking, the aim is a prophylactic analgesia.
Like other opioids (hydromor-phone, meperidine, pentazocine, codeine), morphine is rapidly eliminated, limiting its duration of action to approx. 4 h. To maintain a steady analgesic effect, these drugs need to be given every 4 h. Frequent dosing, including at nighttime, is a major inconvenience for chronic pain patients. Raising the individual dose would permit the dosing interval to be lengthened; however, it would also lead to transient peaks above the therapeutically required plasma level with the attending risk of unwanted toxic effects and tolerance development Preferred alternatives include the use of controlled-release preparations of morphine, a fentanyl adhesive patch, or a longer-acting opi-oid such as /-methadone. The kinetic properties of the latter, however, necessitate adjustment of dosage in the course of treatment, because low dosage during the first days of treatment fails to provide pain relief, whereas high dosage of the drug, if continued, will lead to accumulation into a toxic concentration range (C).
When the oral route is unavailable opioids may be administered by continuous infusion (pump) and when appropriate under control by the patient - advantage: constant therapeutic plasma level; disadvantage: indwelling catheter. When constipation becomes intolerable morphin can be applied near the spinal cord permitting strong analgesic effect at much lower total dosage.
I K Nalbuphine
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