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Unit I: Pain and Symptom Management
Module 3, Part 5. Opioid Adverse Effects

Introduction:

 Opioids have many possible adverse effects; some are common, some not. Although opioids do not cause any direct end-organ toxicity (eg., hepatic, renal, pancreatic insufficiency), certain side effects such as constipation are predictable and should be treated "pre-emptively."

Addiction (psychological dependence), tolerance, and physical dependence are not considered among the adverse effects. The ethical considerations of “double effect” and unintended consequences of opioids and other medications is discussed in Unit IV: Ethical and Legal Issues.
Opioid allergy: Many people believe that opioid-induced nausea/vomiting, constipation, drowsiness, or even confusion is an allergic reaction. However, these are not allergic reactions; they are adverse effects. While one or more may present on initial dosing, adverse effects can be easily managed and patients generally develop pharmacologic tolerance to all but constipation within a relatively brief period.

Anaphylactic or true allergic reactions to opioids are rare. Urticaria and bronchospasm could be direct opioid effects or signs of allergy. Sudden onset of breathlessness or other signs of anaphylaxis should be taken very seriously, and the offending opioid replaced with another from a different class.
Urticaria, pruritus In some patients, opioids produce urticaria or pruritus. These effects are the result of mast cell destabilization by the opioid and subsequent histamine release. Usually the rash and pruritus can be managed by routine administration of long-acting, non-sedating antihistamines (e.g., fexofenadine, 60 mg po bid; diphenhydramine, loratadine, or doxepin, 10–30 mg po q hs) while opioid dosing continues .
Constipation Constipation secondary to opioid administration is almost universal. It is primarily the result of opioid effects on the central nervous system, spinal cord, and myenteric plexus of the gut that, in turn, reduce gut motor activity and increase stool transit time. The colon has more time to desiccate its contents, leaving large hard stools that are difficult to pass. Other factors, such as dehydration, poor food intake, and certain medications may make the problem worse. 

Important points to remember:

  • Tolerance to constipation may develop very slowly, if at all. 
  • Opioid-induced constipation requires anticipatory and ongoing management. 
    • "THE HAND THAT WRITES THE NARCOTIC ORDER SHOULD, UNLESS THERE IS A CONTRA-INDICATION, WRITE A LAXATIVE ORDER" (N. MacDonald, Canadian Palliative Care Curriculum, 1991)
    • Opioid bowel syndrome: You would much rather prevent this condition than to treat it.
    • Dietary interventions alone (eg, increase fluid and fiber) are often insufficient. 
    • Bulk-forming agents (eg, psyllium) require substantial fluid intake and are not recommended for those with advanced disease and poor mobility. 
  • To counteract the slowing effect of opioids, start by prescribing a routine stimulant laxative (eg, senna, bisacodyl, glycerine, casanthranol, etc) and escalate the dose to effect. 
  • While stool softeners (eg, docusate sodium) are not usually effective by themselves, combination stimulant/softeners (eg, senna + docusate sodium or calcium) can be useful. 
  • A prokinetic agent (e.g., metoclopramide) may also significantly counteract the opioid effect. 
  • If constipation persists, some patients will benefit from the addition of an osmotic agent, such as milk of magnesia, lactulose, or sorbitol, to increase the stool’s moisture content. If the constipation proves to be refractory to basic therapy, interventions that are more aggressive may be necessary (see Unit I, Module 4: Nausea, Vomiting, Constipation).
Nausea/vomiting Many patients starting opioids experience nausea with or without vomiting. It is easily anticipated and treated with antiemetics and usually disappears as tolerance develops within a few days. Young women seem to be most at risk. Dopamine-blocking agents (eg, prochlorperazine, 10 mg before opioid and q 6 h; haloperidol, 1 mg before opioid and q 6 h; metoclopramide, 10 mg before opioid and q 6 h) are most often effective. In refractory cases, a more aggressive approach or an alternative opioid may become necessary (see Unit I, Module 4: Nausea, Vomiting, Constipation).
Sedation Patients sometimes complain of feeling sedated or mentally clouded immediately after beginning an opioid analgesic. Care must be taken to distinguish true sedation (inability to fully wake up) from exhaustion due to previous sleep deprivation with the unrelieved pain (sleeps a lot, but is able to wake fully between sleeps). Opioid-induced sedation usually disappears over a few days as tolerance develops. Most patients also catch up on their lost sleep over a week or two. 

For patients with very advanced disease, mental clouding and excessive somnolence are often issues, particularly when patients have multiple concomitant medical conditions, medications, and declining function, even in the absence of opioid analgesics. Pain may, in fact, be the primary stimulant keeping them alert. Once pain is managed, the patient’s “natural” level of sedation may become apparent. If sedation occurs, encourage patients and families to clearly articulate their goals and develop a pain management plan that balances alertness and pain control to suit the individual. Some patients may prefer to be sleepy and comfortable, rather than alert and in pain. 

If undesired sedation persists, a different opioid or an alternate route of administration may provide relief. Also, consider the use of a psychostimulant (eg, methylphenidate, 5 mg q am and q noon and titrate), particularly if the opioid is providing effective analgesia.

Delirium The onset of confusion, bad dreams, hallucinations, restlessness, agitation, myoclonic jerks, a significantly depressed level of consciousness, or seizures suggests delirium due to opioid excess. If opioid dosing guidelines are followed closely, delirium rarely occurs in patients who have normal renal clearance. However, one or more of these adverse effects may present gradually (eg, in the patient who is not passing much urine and is accumulating opioid due to decreased intake or dehydration) or rapidly (eg, in the patient who is developing sepsis) (see Unit I, Module 5: Altered Mental States and Delirium).
 
Respiratory depression Many physicians have an exaggerated view of the risk of respiratory depression when using opioids to relieve pain. The inappropriate application of animal and human models from acute pain research is in part responsible for this fear. Pain is a potent stimulus to breathe, and pharmacologic tolerance to respiratory depression develops quickly. Opioid effects are quite different from those experienced by a patient who is not in pain and receives similar doses. 

As doses increase, respiratory depression does not occur suddenly in the absence of overdose. Somnolence always precedes respiratory depression. Adequate ongoing assessment and appropriate titration of opioids based on pharmacologic principles will prevent misadventures.  

Risk factors associated with respiratory depression include:

  • Opioid naïve
  • IV administration
  • Rapid dose escalation
  • Removal of the painful stimulus
  • Relative risk: chronic lung disease (CO2 retention), renal dysfunction.

Patient-controlled analgesia (PCA) with an appropriate dosing interval (10–15 minutes if IV, 30 minutes if SC) can be used safely, because the patient who takes too many extra doses of opioid will fall asleep and stop pushing the button before respiratory depression occurs. If delirium due to opioid excess does occur, but respirations are not compromised (> 6/min), the routine opioids may be stopped and the patient appropriately hydrated or sepsis managed until the adverse effects abate. 

Use of Naloxone:

If respirations are compromised (< 6/min), naloxone may be necessary if it is the goal of care to keep the patient alert while treating the underlying cause. 

  • Dilute 0.4 mg of naloxone to 10 mL with sterile water. Administer 0.1 to 0.2 mg IV q 1 to 2 min until the patient is alert. 
  • As the effective plasma half-life is short (10 to 15 minutes) because of naloxone’s high affinity for lipids, monitor the patient closely every few minutes for recurrent drowsiness. 
  • If drowsiness recurs, repeat dosing as required until the patient is no longer compromised.

To Continue on to Part 6 of this module, CLICK HERE.

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