Opioid adverse reactions

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Adverse Reactions

Opioid analgesics may cause more drug toxicity, at least in geriatrics, than non-selective inhibitors of cyclooxygenase (non-steroidal anti-inflammatory agents) or cyclooxygenase 2 inhibitors.[1]

Oxycodone and codeine may increase mortality relative to codeine and hydrocodone[2] and may cause more drug toxicity in geriatrics than codeine or hydrocodone.[2] In contrast to hydrocodone, oxycodone and codeine and metabolized by cytochrome P-450 CYP2D6 which may lead to variable pharmacokinetics due to single-nucleotide polymorphisms and drug interactions.[3]

Opioid analgesics, with long-term use, 80% of patients may have drug toxicity, most commonly gastrointestinal. In addition, substance abuse and "aberrant medication-taking behaviors" may occur.[4]

Serious drug toxicity from long-term use may be low according to one systematic review.[5]

Common adverse reactions in patients taking opioids for pain relief:

These include: nausea and vomiting, drowsiness, dry mouth, miosis, and constipation. Fortunately, most of these are not a problem (see Treating Opioid Adverse Effects below).

Infrequent adverse reactions in patient taking opioids for pain relief:

These include: dose-related respiratory depression (see below), 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).

Gastroparesis

Opioid use may be associated with gastroparesis[6], possibly via stimulation of μ (MOP; β-endorphin) and maybe δ (DOP; enkephalin) receptors.

Codeine may be more likely to affect the gastrointestinal tract[7].

Buprenorphine, a partial agonist at the μ receptor, has also been reported to cause gastroparesis[8].

The affect of tramadol is not clear[9].

Treatment may include sympatholyic medications such as acute phentolamine or chronic clonidine[10].

Male hypogonadism

Chronic opioids may cause male hypogonadism.[11][12]

Employability

Use of opioids may be a risk factor for failing to return to work.[13][14]

In addition, lack of employment may be a predictor of aberrant use of prescription opioids.[15]

Impaired judgment

Opioids may increase risk of traffic accidents[16] and accidental falls[17].

Opioid Induced Hyperalgesia

Opioid-induced hyperalgesia is a phenomenon associated with the long term use of opioids such as morphine, hydrocodone, oxycodone, and methadone. Opioid-induced hyperalgesia has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some palliative care patients, most often when dose is escalated rapidly. [18] [19] If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. [20] [21]

Mortality and Overdose

Death from overdose on opioids may be more common than traffic accidents in the United States.[22] The rate of overdose is increasing faster among women and men according to the Centers for Disease Controll.[23]

Chronic use of the equivalent of more than 20 mg/day of morphine may lead to unintentional or intentional overdose.[24]

Overdose may be more common with with doses equivalent to more than 100 mg/day of morphine.[25] Overdose may[26] or may not[25] be increased with long acting opioids.

In veterinary medicine, there is a maximum effective analgesic dose of buprenorphine, although the frequency of administration may usefully be increased.[27]


Other adverse effects

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 [28] and the online palliative care formulary available on Palliativedrugs.com.)

Nausea: tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3mg once at night) are very effective.

Vomiting: if this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation) then this can be managed with a prokinetic (e.g. domperidone or metoclopramide 10mg every eight hours), but usually needs to be started by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone).

Drowsiness: tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps.

Constipation: this 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 [with 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.

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.

Reversing the effect of opioids: Opioid effects can be rapidly reversed with an opioid antagonist 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. 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 microg) but giving this in small doses (e.g. naloxone 40 microg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief.

How safe are opioids? A world view

There are a number of paradoxical beliefs about opioids:

  • 33% of UK doctors believe they had possibly shortened life during alleviation of symptoms,[29] and yet a follow-up study showed that UK doctors are particularly cautious about shortening life.[30]
  • There is a belief that the use of opioids in pain is a fine balance between relief and hastening death, and yet palliative care physicians do not find themselves faced with the dilemma of relieving symptoms at the risk of shortening life.[31]
  • The Dutch public equate high dose morphine and sedation with euthanasia,[32] and yet it is the least used class of drug used for euthanasia in the Netherlands.

However, studies around the globe 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,[33] and that sedative dose increases were not associated with shortened survival (n=237).[34] Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).[35] In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.[36] In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.[37] The survival of Japanse patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs.[38] In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).[39] Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).[40] 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.[41] Even when opioids are given intravenously, respiratory depression is not seen.[42]

Using opioids safely

  • Starting doses: a person who has never been on analgesics would be started on oral morphine 2.5–5mg every four hours (or morphine by injection 1–2.5mg every four hours). Higher doses can be used if the patient was already on weaker analgesics.
  • Titration: this describes the adjustment of a drug dose to a patient, while allowing the patient’s body time to adjust to the drug to minimise adverse effects. Titration is done in 25–50% steps every 1–2 days.
  • Safety margin of opioids: morphine and diamorphine have a wide safety margin or "therapeutic range".
  • Dose range: this is very wide but usually lies between 30–500mg per 24 hours of oral morphine, but with a median of 90mg (or 15mg every four hours). 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.[43]
  • When discontinuing opioids in tolerant users, a taper of buprenorphine over 4 weeks may be used.[44]

Double effect

The principle of double effect is not used in palliative care. Doctors are not faced with the dilemma of giving a potentially lethal drug dose to a distressed patient.[45]

A palliative care doctor gives repeated, small doses of one or more drugs, each titrated to an individual until the symptoms are eased, while doing everything possible to avoid toxicity. Doctors who give 30–60 times the required dose of morphine or diamorphine, usually as a single intravenous dose, are acting either negligently or maliciously. Since drug records should exist for opioids, there is a clear audit trail to follow if a subsequent investigation is required.

With exceptions such as Shipman, UK doctors are very cautious about shortening life.[46] The persistent belief that opioids and sedatives shorten life or hasten death stems from the experiences of bad practice in the use of the drugs. Evidence in the last 20 years has shown that opioids and sedatives are safe when following palliative care protocols. Clinicians who believe otherwise should be challenged to provide robust clinical evidence to support their view.

References

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  27. need to dig up the Cornell handbook
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