Always ensure opioid doses are carefully titrated ('fine-tuned') to maximise analgesia and minimise side effects.[1]

Side effects that start whilst on regular doses of strong opioid may be due to:

• dehydration or renal failure
• other change in disease status e.g. hepatic function, weight loss
• pain relieved by other methods[2]
• co-administration of amitriptyline - increases the bioavailability of morphine[3,4] leading to opioid side-effects

General management

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

• treat the side effect
• use an alternative opioid
• use an alternative analgesic method
• spinal opioids - may cause less systemic or central side-effects
• parenteral rehydration - may help neuropsychiatric toxicity (hallucination, sedation, myoclonus)[5]

Drowsiness & cognitive impairment

Initial mild drowsiness on initiating opioid therapy will often abate over a few days as the patient adjusts; in this case it is often appropriate to wait for the drowsiness to wear off.

For persistent drowsiness, sedation or subtler cognitive impairment:

• parenteral rehydration if appropriate
• alternative opioid
• psychostimulants have been used to combat sedation.

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 which increase the risk of opioid toxicity. Myoclonus may be more likely in patients also taking antidepressants, antipsychotics or NSAIDs.[6]

• parenteral rehydration if appropriate
• review other medication which may exacerbate myoclonus
• alternative opioid[7]
• clonazepam 2-8mg/24h[8,9]
• diazepam or midazolam probably less effective than clonazepam but may be appropriate if sedation is also desirable
• gabapentin 600-1200mg/24h divided doses may help opioid-induced myoclonus[10]

Constipation

• constipation can usually be treated acceptably with laxatives
• fentanyl causes less constipation than morphine if change needed

Paradoxical pain

Hyperalgesia and allodynia have been reported with high-dose morphine.[5,11-13] It is usually associated with myoclonus, and an increase in the morphine dose may lead to worsening of the pain, thus it has been called paradoxical pain.[14,15] It is reported most frequently with morphine, but other opioids including sufentanil (similar to fentanyl) have been implicated.[16] Substitution of an alternative opioid often resolves the symptoms.

Switching to methadone has been reported most effective, but a reduction of dose and addition of an alternative co-analgesic e.g. ketamine or clonazepam may also be tried.

Nausea & vomiting

Initial nausea & vomiting may wear off after a week and usually responds to:

• haloperidol 1.5mg nocte
• metoclopramide may be needed for opioid-induced gastric stasis, and
• cyclizine or 5-HT₃ antagonists may be helpful in other patients
• alternative opioid

Sweating

• alternative opioids
• exclude other causes of sweating
• antimuscarinic drugs

Pruritus (itching)

More common with spinal opioids but can occur with systemic.

• alternative opioids
• if unsuccessful, treat pruritus with 5-HT₃ antagonists or paroxetine

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 is only indicated if significant respiratory depression is present; opioid withdrawal symptoms and pain can be severe in patients on long-term opioids.[17]
• It is important to titrate the dose carefully, so as not to produce an acute opioid withdrawal.
• 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.

Naloxone

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% on pulse oximeter

Use of naloxone[18]

• Dilute Naloxone 0.4mg vial in 10mL saline for injection.
• Use an IV cannula or butterfly.
• Administer 0.5mL IV every 2 minutes until respiratory status satisfactory.
• Repeat further doses as needed.