Side effects of opioids

Common Side Effects

Most common side effects are predictable consequences of opioid pharmacological actions and include nausea, vomiting, constipation, pruritus, dizziness, dry mouth and sedation.

• Side effects are extremely common with opioid therapy.
• Between 50% and 80% of patients in clinical trials experience at least one side effect from opioid therapy, however in everyday use the incidence may be even higher.
• Adverse events frequently lead to discontinuation of opioid therapy. Most side effects, with the exception of constipation and itching, improve shortly after initiation of treatment or following an intended dose increase. Constipation and itching tend to persist throughout treatment and may require long-term management.
• Opioids have multiple effects on respiratory physiology, including decreased central respiratory drive, respiratory rate, and tidal volume. They also increase airway resistance and decrease the patency of the upper airways. The consequence of all of these effects may lead to ineffective ventilation and upper airway obstruction in susceptible individuals.
• Respiratory depression is a much-feared harm associated with the use of opioids. It is mostly a concern in acute pain management where patients have not developed tolerance. For persistent pain it is most likely to be a potential problem if there has been a large, often unintended dose increase, or changes in formulation or route of administration.
• Opioids can cause irregular respiratory pauses and gasping may lead to erratic breathing and significant variability in respiratory rate. The respiratory effects of opioids are more pronounced during sleep. Fatalities have been reported in patients with obstructive sleep apnoea who are prescribed opioids and sleep apnoea may be a relative contraindication to opioid therapy. This is particularly important if patients are taking other central respiratory depressants such as benzodiazepines. If opioids are prescribed to patients with obstructive sleep apnoea they will need up to date assessment of nocturnal respiratory function and should be compliant with therapy for this eg, continuous positive airway pressure. Patients with sleep apnoea being prescribed opioids will need regular and detailed assessment of treatment.
• There is little evidence that, in equi-analgesic doses, commonly used opioids differ markedly in the incidence of their side effects.
• Patients using intermittent opioid dosing regimens might not become tolerant to side effects.
• Increased absorption may occur from transdermal opioid formulations with a fever or other intercurrent illness, and if the patient is exposed to external heat, for example a hot bath or sauna. If concerns arise, closer patient monitoring will be required.
• Inadequate management of side effects (intractable constipation, faecal impaction, bowel obstruction) and consequences of opioid treatment (falls, fractures and acute confusional state) may contribute to unplanned hospital admissions and contribute to the overall costs associated with opioid treatment

Further Reading 

• Kalso E, Edwards J, Moore R, McQuay H: Opioids in chronic non-cancer pain: Systematic review of efficacy and safety. Pain 2004; 112:372-380
• Moore RA, McQuay HJ: Prevalence of opioid adverse events in chronic non-malignant pain: Systematic review of randomised trials of oral opioids. Arthritis Research &Theory. 2005; 7: R1046–R1051.
• Pattinson K. T. S. Opioids and the control of respiration.British Journal of Anaesthesia. 2008;6:747-758.  
• Webster LR, Choi Y, Desai H, et al. Sleep-disordered breathing and chronic opioid therapy. Pain Medicine 2008;9:425-32.

Management of Opioid Related Side Effects

Most common side effects are predictable consequences of opioid pharmacological actions and include nausea, vomiting, constipation, pruritus, dizziness, dry mouth and sedation

• Opioid-associated side effects should be anticipated and appropriate counselling about common side effects and their management should be provided to patients before the first prescription.
• Tolerance to many side effects usually occurs within the first few days of initiating treatment; however unlike other side effects pruritus and constipation tend to persist throughout treatment.
• Common gastrointestinal side effects should be predicted and prophylactic treatments considered if appropriate
• A small supply of an anti-emetic (eg, cyclizine, prochlorperazine) may be beneficial when providing the initial prescription of an opioid.
• Encouraging the patient to drink lots of fluid, and to eat additional fruit and fibre may minimise constipation, however a combination of stool softener (eg, docusate sodium) and a stimulant laxative (eg, senna or bisacodyl) is often necessary.
• Peripherally restricted opioid antagonists (such as oral naloxegol, oral prolonged release naloxone in combination with prolonged release oxycodone, and subcutaneous methylnaltrexone) have modest benefit for improving constipation when compared with placebo, however there are many fewer data compared with regular optimal laxative therapy and life style advice. These products have a limited place in the management of opioid induced bowel symptoms and constipation after an adequate trial of other options.

• Central side effects, such as drowsiness and dizziness, also tend to improve gradually after opioid initiation, however patients should be counselled about the possible effects on driving and other skilled tasks involving co-ordination and concentration when  initiating or increasing an opioid dose.
• Patients should be warned of the likelihood of enhanced effects and risks associated with concomitant use of other medicines and substances with sedative properties, including alcohol.

Further Reading

•   Chey WD, Webster L, Sostek M, et al. Naloxegol for Opioid-Induced Constipation in Patients with Noncancer Pain.  New England Journal of Medicine 2014; 370: 2387-2396.
•   Simpson K, Leyendecker P, Hopp M, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Current Medical Research and Opinion 2008; 24:  3503-3512.
•   Twycross R, Sykes N, Mihalyo M, et al. Stimulant laxatives and opioid-induced constipation. Journal of Pain and Symptom Management. 2012; 43: 306-13.

The Cost of Opioid Related Side Effects

• Direct costs associated with opioid related side effects accumulate as a result of the need for prescribing medicines to prevent or minimise side effects and increased healthcare use (GP consultations, Emergency Department visits, unplanned hospital admissions).
• Impaired physical, psychological and social functioning (assessed by reduced quality of life), and work absences contribute to indirect costs.
• Given the high incidence and large economic burden of opioid-related side effects, prevention rather than treatment may be cost-effective.
• Opioid-related side effects are common in hospitalised patients and may contribute to increased length of stay and costs of admission

Further Reading

•  Anastassopoulos KP, Chow W, Tapia CI, et al. Economic study on the impact of side effects in patients taking oxycodone controlled-release for noncancer pain. Journal of Managed Care Pharmacy 2012; 18: 615-26.
• Annemanns L. Pharmacoeconomic impact of adverse events of long-term opioid treatment for the management of persistent pain. Clinical Drug Investigation 2011; 31: 73-86.