- To have an understanding of the main opioids used in the management of acute pain
- To know the principle side effects associated with taking opioids
- To understand opioids mechanism of action
- To recognise the use of naloxone and its role
The first source of opiates was opium which is obtained from the unripe seed capsule of the poppy (Papaver somniferum) which yields a milky juice. Although morphine is still obtained from natural sources, there are now many chemical substances available with similar analgesic, sedative and mood-elevating effects. Most are synthetic although some are derived from morphine (codeine is methylmorphine and diamorphine is diacetylmorphine). The naturally occurring substances tend to be called opiates, and the synthetic agents opioids.
Mechanism of action
Endogenous opioids are substances that are naturally occurring in the body and help modulate the pain experience. Opioids work by binding to receptors found in the brain, spinal cord and other nervous tissue which are normally activated by endogenous enkephalins and endorphins. There is considerable debate over the nature of these, but there is general acceptance of the presence of μ, κ and δ receptors (pronounced mu, kappa and delta), and there may be subtypes of each category pcc1032. It has been suggested that μ receptors are responsible at supraspinal sites for analgesia, sedation and respiratory depression. κ receptors have been associated with analgesia produced at spinal sites.
Some opioids (e.g. pentazocine) can produce disturbing effects including dysphoria, hypertonia, tachycardia, tachypnoea and mydriasis perhaps mediated by another opioid σ (sigma) receptor. The opiates and opioids have different activities at these receptors. The agonists bind to opioid receptors and excite them. The agonist/antagonists (pentazocine) bind to opioid receptors, and are analgesics, but excite only some receptors (κ) and so can antagonise morphine and similar drugs in some situations.
The partial agonists (buprenorphine) bind with great affinity to μ receptors but excite them less than the pure agonists. The pure antagonists (naloxone) bind to receptors but have no activity at them and can be used to reverse the effects of drugs like morphine. Naloxone may not completely antagonise the effects of the partial agonist drug buprenorphine which has a very high receptor affinity. The synthetic agonist/antagonists act via stimulation of κ receptors at spinal sites and the expectation was that they would provide potent analgesia but without the sedation and respiratory depression of morphine. However, such specificity has not been achieved. The possibility exists that mixed agonist/antagonists like pentazocine can reverse the analgesic effect of pure agonists when given in combination.
Management of pain
Opioid analgesics, including morphine are the cornerstone for management of moderate to severe acute pain. Effective use of these agents may help facilitate postoperative activities such as coughing, deep breathing exercises, ambulation, and physical therapy. Morphine is the standard agent for opioid therapy. If morphine cannot be used because of an unusual reaction or allergy, another opioid can be substituted. Patients vary greatly in their analgesic dose requirements and responses to opioid analgesics. Intravenous administration is the parenteral route of choice after major surgery. This route is suitable for bolus administration and continuous infusion (including PCA).
Specific drugs – Pure agonists
Morphine is the standard opioid analgesic and is the main phenanthrene derivative of opium and is metabolised to morphine-6-glucuronide, which is a potent analgesic, and also to morphine-3-glucuronide, which has no analgesic effects and may act as a pharmacological modulator.
The diverse pharmacological effects of morphine include analgesia, sedation, nausea and vomiting, respiratory depression, bradycardia, miosis, euphoria, depression of gastrointestinal motility, pruritus and urinary retention . Patients with poor renal failure may become very drowsy because of the accumulation of morphine-3-glucuronide . Ninety per cent of a dose of morphine is excreted within 24 hours. Morphine is discussed extensively here to provide a basis for comparison with the other opioids.
Morphine is absorbed well from the gastrointestinal tract but first-pass metabolism in the liver means that the oral bioavailability is only 25%. After intramuscular or subcutaneous administration, peak blood levels are attained within 30 – 45 minutes, and can provide the analgesia for 3 – 4 hours. Intravenous morphine acts more rapidly but the difference is not as obvious as with the more lipid-soluble opioids like fentanyl. The primary site of action of morphine is in the central nervous system, but only small quantities of a dose pass through the blood-brain barrier. However, there is now evidence that it can act on periperpheral sites following tissue damage .
Morphine has a number of side effects and these may limit its use. Reflect on the side effects and consider strategies that can help reduce or prevent these side effects. Remember, there is no point stopping an opioid and allowing patients to experience severe pain because severe pain has similar consequences to the side effects of opioids. For instance, severe pain will prevent deep breathing and coughing leading to poor oxygenation, sedation and the potential for respiratory depression and arrest. You may like to think of other consequences and reflect on these.
Your list of side effects may reflect the list below:
- Central nervous system effects – morphine produces sedation, mental relaxation and euphoria as well as analgesia.
- Nausea and vomiting – morphine produces nausea and vomiting by stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle, perhaps by activation of dopamine receptors. Interestingly, the direct effect of morphine on the vomiting centre is inhibitory. After morphine, nausea and vomiting are much more common in ambulatory than recumbent patients.
- Respiratory – morphine depresses the respiratory rate and minute ventilatory volume. This is most likely to occur approximately 10 minutes after intravenous and 30 minutes after intramuscular injection. Morphine impairs the response of the brain stem to carbon dioxide by activation of μ receptors. It has been suggested that μ1 receptors subserve analgesia, and μ2 respiratory depression, and that morphine stimulates both. Morphine produces an antitussive effect. However, there can be a preoccupation with respiratory depression and this has been used to justify the lack of appropriate prescriptions of morphine for patients in pain. Patients maintained on oral morphine without respiratory depression who then receive successful nerve blocks must have their morphine dose reduced otherwise respiratory depression may occur in the absence of pain.
- Cardiovascular – the administration of morphine to supine patients has little effect on blood pressure, but there is considerable peripheral vasodilatation. If the patient is standing, morphine may produce orthostatic hypotension due to inhibition of sympathetic outflow, diminishing any compensatory tachycardia for the vasodilatation. Morphine releases histamine and this may explain in part the arteriolar and venous relaxation. In addition, morphine may reduce heart rate both by increased vagal tone and by direct suppression of the activity of the sinoatrial node.
- Gastrointestinal – in general morphine decreases smooth muscle propulsive activity and increases the tone of sphincters in the gut. The slowed gastrointestinal transit means that water absorption in the colon is increased. Constipation is a common side effect of morphine administration. In the biliary tract (as in the bladder and ureter), morphine increases tone and constricts the sphincter of Oddi, which may worsen biliary spasm.
- Miosis – morphine produces pupillary constriction by stimulation of the Edinger-Westphal nucleus. Pinpoint pupils are characteristic features of morphine overdosage but are not always present.
- Cutaneous – morphine dilates cutaneous blood vessels and the skin of the face neck and upper chest may become flushed. This may be due to histamine release, which may also account for urticaria at the injection site. Morphine may also produce pruritus, especially when given spinally and can be reversed by small doses of naloxone.
We know the side effects of morphine but we are also aware that morphine is extremely useful to manage severe postoperative pain. Given this knowledge, it is surprising therefore, that more preventative management is not undertaken in anticipation of the side effects. For instance, better postoperative fluid management for hypotension, stool softener and laxative for constipation, regular and appropriate antiemetics for PONV etc.
Diamorphine is diacetylmorphine and the parent structure has no opioid activity. Tissue and plasma esterases metabolise diamorphine to monoacetylmorphine; both are more lipid soluble than morphine and cross the blood-brain barrier more easily. In the central nervous system diamorphine and monoacetylmorphine are converted to the active morphine molecule. Diamorphine may be a more euphoriant drug than morphine and may produce less nausea. In many countries diamorphine is unavailable as it is considered to be a dangerous drug of abuse. However, used appropriately, it should not cause addiction. As diamorphine is more soluble than morphine it can be injected in smaller volumes; this is an advantage in cachectic patients and for subcutaneous use.
Codeine is methylmorphine and the methyl group at the C3 position increases the oral bioavailability of the compound, but as it is less effective than morphine it is used for mild to moderate pain. Moore & McQuay  have shown that it is not an effective analgesic for postoperative pain with an NNT of 16.7 for at least 50% pain relief over 4 to 6 hours compared with placebo in pain of moderate to severe intensity . Interestingly, however, when 60mg codeine is combined with 1000mg paracetamol the NNT drops to 2.2. Codeine has a low abuse potential and is often used in oral preparations in combination with non-opioid narcotics. The side-effect profile of codeine, a weak opioid, is the same as with a strong opioid.
Dihydrocodeine, is a synthetic opioid analgesic which was developed in the early 1900s. Its structure and pharmacokinetics are similar to codeine and it is used for the treatment of postoperative pain and as an antitussive. In 1995, nearly one tenth of all analgesic preparations issued in England were for dihydrocodeine . A single 30mg oral dose of dihydrocodeine does not provide effective analgesia and a 60mg dose is significantly less effective than ibuprofen 400mg. Therefore, patients should be offered a more effective analgesic in the treatment of postoperative pain . Doses in excess of the recommended 30-mg every 4 hours may be associated with nausea and vomiting.
The phenylpiperidine compound pethidine is an effective analgesic but some of its clinical effects are quite different from morphine. It is shorter acting than morphine and produces less sedation and pupillary constriction than morphine; the latter is related to an atropine-like effect, which also results in the patient having a dry mouth. For postoperative pain relief, the NNT for 100mgs of intramuscular pethidine for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain compared with placebo is 2.9 . Based on small numbers of patients, pethidine 50mgs does not appear to offer effective pain relief. In the cardiovascular system blood pressure may fall with pethidine and a tachycardia may be observed. Pethidine is metabolised in the liver and one metabolite, norpethidine, may accumulate with prolonged or high dosage or with impaired renal clearance, producing tremor, twitching, agitation and convulsions . Pethidine should not be used in patients who have recently taken monoamine oxidase inhibitors as a serious interaction can develop with convulsions and coma, unstable blood pressure and high temperatures. Due to its high first pass metabolism, oral pethidine is similar in potency to codeine. Therefore, given that pethidine is not associated with any specific advantage over morphine, it is a poor choice if multiple doses are needed .
Fentanyl is a synthetic opioid agonist that is related to the phenylpiperidines. It is a highly potent and lipid-soluble opioid, which is mainly used by intravenous injection as a component of general anaesthesia. As an analgesic it is some 100 times more potent than morphine. A single intravenous dose of fentanyl has a more rapid action (5 – 6 minutes) than morphine, reflecting the greater lipid solubility, which also accounts for a rapid redistribution around the body and a short duration of effect. With multiple doses or continuous infusions of fentanyl, saturation of the body tissues may occur and the duration of effect and side effects such as ventilatory depression may be prolonged. Fentanyl does not affect arterial blood pressure; even with high doses histamine is not released, but cardiac output can fall due to bradycardia. Secondary peaks in plasma fentanyl concentration can occur, with respiratory depression, due to gastric sequestration or release from muscle or the lungs after anaesthesia. Fentanyl can be used safely by epidural administration for postoperative pain relief as localisation in the fatty tissues and rapid absorption into the blood stream of the spinal cord prevents rostral spread, i.e., the drug will spread upwards towards the brain. The high lipid solubility of this drug has encouraged the recent development of transdermal fentanyl patches but these are not commonly seen in the acute pain setting, as they should not be used in patients who are opioid naïve. It has also been shown to be beneficial when combined with bupivacaine for wound infiltration .
Tramadol is aphenyl-substituted aminometyl-cyclohexanol derivative. It is classed as a weak opioid and as such is often used as a step-down analgesic from morphine. It appears to be a useful analgesic with minimal sedative effects or abuse potential, but it is weaker than morphine . A dose of 100mg has an NNT of 4.6 for at least 50% pain relief over 4-6 hours in patients with moderate to severe pain compared with placebo , however this is also reduced when combined with paracetamol 1g. The mechanism of action of tramadol is not understood fully, but it is an agonist at opioid receptors and also has a spinal action on noradrenergic pathways. Tramadol inhibits neural uptake of noradrenaline and serotonin. Tramadol is available in oral and parenteral forms.
Specific drugs – Mixed agonist/antagonists
These opioids produce analgesia by agonist activity at κ receptors. They are not agonists at μ receptors, where they are competitive antagonists instead. In general they are weaker analgesics than the pure agonists and so have not found widespread use in clinical practice. In contrast to the linear dose-response relationship of the pure agonists, this group tends to have a ceiling to their analgesic effect and an increase in dose may only result in more side-effects. Use of the agonist/antagonists is associated with dysphoria perhaps due to activity at δ opioid receptors. They are reversed by naloxone, but the agonist/antagonists can also act as inhibitors of the analgesic effect of pure agonists by competitive antagonism at μ receptors.
Pentazocine is a benzomorphan derivative and has a quarter of the analgesic potency of morphine. It is most often used for the relief of mild to moderate pain and can be given in similar doses orally or by injection. It has a much lower abuse potential than pure agonists, but chronic ingestion may produce dependence. It can precipitate withdrawal symptoms in patients physically dependent on pure agonist opioids. Dysphoria can present with hallucinations and thought disturbances. Intravenous pentazocine increases sympathetic activity and raises heart rate and arterial blood pressure.
Nalbuphine is structurally related to both naloxone and oxymorphone. It is an agonist-antagonist opioid with a spectrum of effects that qualitatively resembles those of pentazocine. It is only available as a parenteral preparation as it undergoes significant first-pass metabolism in the liver when given orally. It is as potent an analgesic as morphine and the respiratory effect is equivalent up to a dose of nalbuphine 30-mg, after which no further depression occurs. The main side effect is sedation, which presents in one-third of patients given nalbuphine. Dysphoria is less common than with pentazocine (as it is a more potent antagonist at μ receptors) but is as unpleasant and increases with the dose of nalbuphine given.
Meptazinol is an agonist-antagonist opioid that is about one tenth as potent as morphine in producing analgesia. The mechanism of action of meptazinol is unclear, but there is some evidence that it is a selective agonist of μ1 receptors, it may also have an effect on central cholinergic pathways and it has opioid antagonistic effects. Meptazinol is associated with less respiratory depression, perhaps as it has less effect on μ2 receptors. Nausea and vomiting are common side effects, the incidence of which can be reduced by anticholinergic drugs such as hyoscine or atropine.
Specific drugs – Partial agonists
Buprenorphine is a semi-synthetic, highly lipophilic opioid derived from thebaine. Buprenorphine is a partial agonist at μ receptors; it has higher affinity for μ receptors but a lower activity at these receptors than the pure agonists. Buprenorphine is 25 to 50 times more potent than morphine, and the recommended intramuscular dose is 0.3 mg, which acts after 30 minutes and lasts for up to 8 hours. Extensive hepatic metabolism means that the bioavailability is low when given orally, but sublingual administration of 0.4mgs of buprenorphine is effective. The adverse effects are similar to morphine but as buprenorphine has very high affinity for μ receptors, it may be only incompletely reversed by naloxone. The major problem with buprenorphine is the high incidence of severe nausea and vomiting experienced especially by patients who are mobile.
Specific drugs – Pure opioid antagonists
Relatively minor changes in the structure of an opioid can convert a drug that is primarily an agonist into one with antagonistic actions at one or more types of opioid receptors. Such structural changes convert oxymorphone to naloxone or naltrexone, which appear devoid of agonistic actions and probably interact with all types of opioid receptors. Naloxone is therefore a competitive antagonist to the analgesics described above. A single dose of 0.4 mg can be used to reverse opioid-induced respiratory depression, but it may be necessary to repeat the dose or give an infusion, as most opioids have longer elimination half-lives than naloxone. Naltrexone has the same mode of action but has a longer half-life and can be given orally in a single daily dose of 50 mg. Naltrexone is used in the treatment of opioid addiction.
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