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Ovid: Oxford Handbook of Palliative Care

Editors: Watson, Max S.; Lucas, Caroline F.; Hoy, Andrew M.; Back, Ian N. Title: Oxford Handbook of Palliative Care, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > Symptom Management > Chapter 6a – The management of pain > Opioid side-effects and toxicity Opioid side-effects and toxicity Thou hast the keys of Paradise, Oh just, subtle, and mighty opium! Thomas De Quincey 1785–1859: Confessions of an English Opium Eater (1822) Patients should be warned of the possible side-effects of morphine such as nausea and drowsiness, which are usually short-lived, and are not often a problem. If drowsiness continues after a few days other possible causes, e.g. uraemia, hypercalcaemia or toxicity from other medication, should be excluded—otherwise seek advice. Constipation is predictable and most patients need prophylactic laxatives. If unacceptable toxicity occurs, reduce morphine dose. The patient may need to miss several doses and restart at a lower dose. Warning signs of morphine toxicity

  • Drowsiness
  • Hallucinations (auditory or visual)
  • Confusion
  • Vomiting
  • Myoclonus
  • Pin point pupils

Always ensure opioid doses are carefully titrated (‘fine-tuned’) to maximize analgesia and minimize side-effects. Opioid toxicity may be increased by:

  • dehydration or renal failure
  • other change in disease status e.g. hepatic function, weight loss
  • pain relieved by other methods
  • co-administration of amitriptyline increases the bioavailability of morphine

General management A number of different approaches may be used to manage persistent opioid-related side-effects:

  • treat the side-effect
  • use an alternative opioid
  • use an alternative analgesic method, such as spinal opioids, which may cause less systemic or central side-effects

Drowsiness and cognitive impairment Initial mild drowsiness on initiating opioid therapy will often abate over a few days as the body adjusts. It is often appropriate to continue opioids and wait for the drowsiness to wear off. For persistent drowsiness or subtler cognitive impairment:

  • Parenteral rehydration, if appropriate, may help neuropsychiatric toxicity (e.g. hallucinations, sedation, myoclonus)
  • P.203

  • Alternative opioid
  • Psychostimulants have been used to combat sedation in specialist units

Hallucinations or delirium

  • Parenteral rehydration, if appropriate
  • Alternative opioid
  • Antipsychotic e.g. haloperidol 3–5mg nocte or by CSCI

Myoclonus Consider renal failure—renal failure alone can cause myoclonus, but also causes opioid metabolites to accumulate, thereby increasing the risk of opioid toxicity. Myoclonus may be more likely in patients also taking antidepressants, antipsychotics or NSAIDs. Consider the following:

  • Parenteral rehydration, if appropriate
  • Review other medication which may exacerbate myoclonus
  • Alternative opioid
  • Clonazepam 2–4mg/24h. Diazepam or midazolam are probably less effective than clonazepam but may be appropriate if sedation is also desirable
  • Gabapentin 600–1200mg/24h in divided doses


  • Constipation can usually be treated acceptably with laxatives
  • Fentanyl may cause less constipation than morphine

Increase in generalized pain Hyperalgesia and allodynia have been reported with high dose opioids. It is usually associated with myoclonus, and an increase in the opioid dose may lead to worsening of the pain. Substitution of an alternative opioid often resolves the symptoms. Alternatively, reduction of dose and the addition of an alternative co-analgesic may be useful. Nausea and vomiting Initial nausea may wear off after a week and usually responds to:

  • Haloperidol 1.5mg nocte
  • Metoclopramide (for opioid-induced gastric stasis)
  • Cyclizine or 5-HT3 antagonists
  • Alternative opioid


  • Alternative opioid
  • Exclude other causes of sweating
  • Antimuscarinic drugs

Pruritus (itching) More common with spinal than with systemic opioids.

  • Alternative opioid
  • If unsuccessful, treat opioid induced pruritus with 5-HT3 antagonists such as ondansetron

Respiratory depression/sedation Reduction of the dose is usually all that is required immediately. Infusion by a syringe driver should be temporarily stopped to allow plasma levels to decrease, before restarting at a lower dose Naloxone

  • Naloxone is only indicated if significant respiratory depression is present; acute opioid withdrawal symptoms and pain can be severe in patients who have been on long-term opioids Naloxone has a half-life of 5–20 minutes. As the half-life of most opioids is longer than this, it is important to continue assessment of the patient and give naloxone at further intervals if necessary

Indications for naloxone:

  • respiratory rate <8 breaths/min, or
  • <10–12 breaths/min, difficult to rouse and clinically cyanosed, or
  • <10–12 breaths/min, difficult to rouse and SaO2<90 per cent on pulse oximeter

Method of use of naloxone

  • Dilute naloxone 0.4mg vial in 10ml 0.9% sodium chloride
  • Use an i/v cannula or butterfly
  • Administer 0.5ml i/v every 2 minutes until respiratory status satisfactory
  • Repeat further doses as needed

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