Opioid Side Effects

Common adverse reactions in patients taking opioids for pain relief include: nausea and vomiting, drowsiness, itching, dry mouth, miosis, and constipation.

Infrequent adverse reactions in patients taking opioids for pain relief include: dose-related respiratory depression (especially with more potent opioids), confusion, hallucinations, delirium, urticaria, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil). If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia.

Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit leukocyte migration. However the relevance of this in the context of pain relief is not known.

Treating opioid adverse effects

Most adverse effects can be managed successfully. For more complete information, see ''Oxford Textbook of Palliative Medicine'' and the online palliative care formulary.

''Nausea'': tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3 mg once at night) are very effective. Stronger antiemetics such as ondansetron or tropisetron may be indicated if nausea is severe or continues for an extended period, although these tend to be avoided due to their high cost unless nausea is really problematic. A cheaper alternative is dopamine antagonists, e.g. domperidone and metoclopramide. Domperidone does not cross the blood-brain barrier, so blocks opioid emetic action in the chemoreceptor trigger zone without adverse central anti-dopaminergic effects. Some antihistamines with anti-cholinergic properties (e.g. orphenadrine or diphenhydramine) may also be effective.

5-HT₃ antagonists (e.g. ondansetron)
Dopamine antagonists (e.g. domperidone)
Anti-cholinergic antihistamines (e.g. diphenhydramine)

''Vomiting'': this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation), besides direct action on the vomiting centre of the brain. Vomiting can thus be prevented by prokinetic agents (e.g. domperidone or metoclopramide 10 mg every eight hours). If vomiting has already started, these drugs need to be administered by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).

Prokinetic agents (e.g. domperidone)
Anti-cholinergic agents (e.g. orphenadrine)

''Drowsiness'': tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps. Certain opioids such as morphine and diamorphine (heroin) tend to be particularly sedating, while others such as oxycodone and meperidine (pethidine) tend to produce less sedation, but individual patients responses can vary markedly and some degree of trial and error may be needed to find the most suitable drug for a particular patient. Treatment is at any rate possible - CNS stimulants are generally effective.

Stimulants (e.g. caffeine, modafinil, amphetamine)

''Itching'': tends not to be a severe problem when opioids are used for pain relief, but if required then antihistamines are useful for counteracting itching. Non-sedating antihistamines such as fexofenadine are preferable so as to avoid increasing opioid induced drowsiness, although some sedating antihistamines such as orphenadrine may be helpful as they produce a synergistic analgesic effect which allows smaller doses of opioids to be used while still producing effective analgesia. For this reason some opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which may also have the added advantage of reducing nausea as well.

Antihistamines (e.g. fexofenadine)

''Constipation'': develops in 99% of patients on opioids and since tolerance to this problem does not develop, nearly all patients on opioids will need a laxative. Over 30 years experience in palliative care has shown that most opioid constipation can be successfully prevented: "Constipation ... is treated laxatives and stool-softeners" (Burton 2004, 277). According to Abse, "It is very important to watch out for constipation, which can be severe" and "can be a very considerable complication" (Abse 1982, 129) if it is ignored. Peripherally acting opioid antagonists such as alvimopan and methylnaltrexone (Relistor) are currently under development which have been found to effectively relieve opioid induced constipation without affecting analgesia or triggering withdrawal symptoms.

For mild cases, a lot of water and fibers might suffice

Stool-softening and peristalsis-promoting laxatives (e.g. docusate in combination with bisacodyl)
Peripherally-acting opioid antagonists (e.g. methylnaltrexone)
High water intake and dietary fibers

''Respiratory depression'': although this is the most serious adverse reaction associated with opioid use it usually is seen with the use of a single, intravenous dose in an opioid-naive patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem. Several drugs have been developed which can block respiratory depression completely even from high doses of potent opioids, without affecting analgesia, although the only respiratory stimulant currently approved for this purpose is doxapram, which has only limited efficacy in this application. Newer drugs such as BIMU-8 and CX-546 may however be much more effective.

Respiratory stimulants: carotid chemoreceptor agonists (e.g. doxapram), 5-HT₄ agonists (e.g. BIMU8), δ-opioid agonists (e.g. BW373U86)
Opioid antagonists (e.g. naloxone)

Finally, ''all'' opioid effects (adverse or otherwise) can readily be reversed with an opioid antagonist (more exactly, an inverse agonist) such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating and/or reversing the agonist effects. However, the elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required, or a longer acting antagonist such as nalmefene may be used. In patients taking opioids regularly it is essential that the opioid is only partially reversed to avoid a severe and distressing reaction of waking in excruciating pain. This is achieved by not giving a full dose (e.g. naloxone 400 μg) but giving this in small doses (e.g. naloxone 40 μg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief.

Safety

Studies over the past 20 years have repeatedly shown opioids to be safe when they are used correctly. In the UK two studies have shown that double doses of bedtime morphine did not increase overnight deaths, and that sedative dose increases were not associated with shortened survival (n=237). Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15). In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival. In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival. The survival of Japanese patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs. In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).

Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial). Injections of morphine given subcutaneously to Canadian patients with restrictive respiratory failure did not change their respiratory rate, respiratory effort, arterial oxygen level, or end-tidal carbon dioxide levels. Even when opioids are given intravenously, respiratory depression is not seen.

Carefully titrating the dose of opioids can provide for effective pain relief while minimizing adverse effects. Morphine and diamorphine have been shown to have a wider therapeutic range or "safety margin" than some other opioids. It is impossible to tell which patients need low doses and which need high doses, so all have to be started on low doses, unless changing from another strong opioid.

intrathecal magnesium and zinc

NMDA antagonists, such as dextromethorphan or ketamine

cholecystokinin antagonists, such as proglumide

Newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.

Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite common due to low magnesium/zinc content in food and use of substances which deplete them including diuretics (such as alcohol, caffeine/theophylline) and smoking. Reducing intake of these substances and taking zinc/magnesium supplements may slow the development of tolerance to opiates.

Dependence

''Dependence'' is characterised by extremely unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued after tolerance has developed. The withdrawal symptoms include severe dysphoria, sweating, nausea, rhinorrea, depression, severe fatigue, vomiting and pain. Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms.

Addiction

''Addiction'' is the process whereby physical and/or psychological dependence develops to a drug - including opioids. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug. Psychological addiction is more common in people taking opioids recreationally, it is rare in patients taking opioids for pain relief.

Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used.

Semisynthetic derivatives

Diacetylmorphine (heroin)
Dihydrocodeine
Hydrocodone
Hydromorphone
Nicomorphine
Oxycodone
Oxymorphone

Synthetic opioids

Anilidopiperidines

Fentanyl
Alphamethylfentanyl
Alfentanil
Sufentanil
Remifentanil
Carfentanyl
Ohmefentanyl

Phenylpiperidines

Pethidine (meperidine)
Ketobemidone
MPPP
Allylprodine
Prodine
PEPAP

Diphenylpropylamine derivatives

Propoxyphene
Dextropropoxyphene
Dextromoramide
Bezitramide
Piritramide
Methadone
Dipipanone
Levomethadyl Acetate (LAAM)
Difenoxin
Diphenoxylate
Loperamide (used for diarrhoea, does not cross the blood-brain barrier)

Benzomorphan derivatives

Dezocine
Pentazocine
Phenazocine

Oripavine derivatives

Buprenorphine
Dihydroetorphine
Etorphine

Morphinan derivatives

Butorphanol
Nalbuphine
Levorphanol
Levomethorphan

Others

Lefetamine
Meptazinol
Tilidine
Tramadol
Tapentadol

Opioid antagonists

Nalmefene
Naloxone
Naltrexone