Opioids for long term pain

The effectiveness of opioids for long term pain

There are now a large number of randomised control trials and systematic reviews that conclude that opioids may reduce pain for some patients in the short and medium term (usually less than 12 weeks) for a number of chronic painful conditions. The trials included in these syntheses are sometimes large and without conventional sources of bias but the results need more detailed analysis to understand the role of opioids in routine clinical practice. This is important because in trials of opioids in chronic pain withdrawal rates due to adverse events are high. For example, with oxycodone in musculoskeletal conditions about 45% withdraw in the first 3 weeks, and about 65% overall.

Understanding how the data from treatment withdrawals are handled is critical for interpreting trial data for use in real life. Conventionally, these withdrawals from clinical trials are dealt with using the “last-observation-carried-forward” (LOCF) method. Very often, patients have pain relief early on, but then cannot take the drug because of adverse effects. So a patient who has pain relief at (say) 3 weeks, but who withdraws from the trial because of adverse effects is recorded as a treatment success as the pain relief at 3 weeks is assumed to have continued had they not withdrawn from the trial. The result is significantly better pain relief at 12 weeks than placebo, but based in part on inferred data from those withdrawing from the trial.

This is critically important for clinical practice as if a drug is stopped because of adverse effects this represents a treatment failure. If trial data are interpreted such that treatment success should include BOTH pain relief at 12 weeks AND ability to keep taking the tablets, then opioids are no better than placebo. EVERY single RCT in chronic pain using this interpretation comes to this same result.

A further limitation of the data from RCTs is that in general, patients in these trials have discrete pain diagnoses and lack many of the physical and emotional co-morbidities of patients seen in clinical practice. Furthermore, progress of therapy in clinical trials is monitored more closely than is usual in clinical practice and dose titration is closely supervised. Data in relation to improved functional outcomes and quality of life as a result of opioid therapy in these trials are sparse.

Given the limited duration of clinical trials, data on efficacy of long term opioid use are available only from case series and open-label extensions of controlled trials. These latter have been systematically reviewed. Open-label extension data suggest that a small proportion of patients may derive continuing benefit from opioids in the long term but the relevance to clinical practice is uncertain as patients with co-morbidities that may predispose to problematic opioid use are generally excluded from clinical trials and evaluation of long term use does not, in these studies, identify potential benefits from placebo effect, benefits of additional therapies or spontaneous resolution of symptoms.

Analysis of open label data does not enable firm conclusions regarding improvement in function or quality of life with long term opioid treatment. Data from prospective cohort studies suggest that opioids retard return to work after injury and may prolong functional recovery or worsen physical functioning. A Danish cross-sectional study has suggested that when comparing opioid users with non-opioid users, opioid use appears to be associated with poorer self-related quality of life and employment status, increased healthcare use, and worse pain. These studies do not demonstrate causality in relation to opioids and poor function in a number of domains but indicate that the hoped for end points of pain reduction and improvement in function are not being met with long term opioid treatment.

There are always challenges when using what we know from clinical trials in routine practice. Clinical trials always have a limited sensitivity, and there are likely to be patients for whom drugs that cannot be shown to be efficacious in RCTs ‘work’ for them. This means that opioids may reasonably be included in the repertoire of cautious attempts to find some therapy that works when all the obvious ones have been tried. Given the harms of prolonged opioid treatment and the probability of therapeutic disappointment in the long term, exploration of opioid therapy for a patient with refractory pain should be planned carefully and closely monitored. With the evidence we have there should be no trial of traditional opioids in chronic pain beyond modest doses over about 2-4 weeks and the therapeutic trial should be informed by important practice points:

Side effects of opioids

Common opioid 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

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.

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

The effectiveness of opioids for long term pain

• American Pain Society and American Academy of Pain Medicine. Guideline for the Use of Chronic Opioid Therapy in Chronic Noncancer Pain: Evidence Review. 2009. 
• Chou R, Turner JA, Devine EB, et al. The effectiveness and risks of long-term opioid therapy for chronic pain: a systematic review. Annals of Internal Medicine 2015; 162: 276-286.
• Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain – United States 2016. Journal of American Medical Association 2016;315: 1624-1645.
• Eriksen J, Sjøgren P, Bruera E. Critical issues on opioids in chronic noncancer pain: an epidemiological study. Pain 2006; 125: 172–179.
• Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. Canadian Medical Association Journal. 2006; 174: 1589-94.
• Hauser W, Bernardy K, Maier C. Long-term opioid therapy in chronic noncancer pain. A systematic review and meta-analysis of efficacy, tolerability and safety in open-label extension trials with study duration of at least 26 weeks. Schmerz 2015; 29: 96-108.
• Kalso E, Edwards JE, Moore RA, et al. Opioids in chronic noncancer pain: systematic review of efficacy and safety. Pain 2004; 112: 372–380.
• Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database of Systematic Reviews 2010; (1): CD006605.
• Sullivan M, Howe C. Opioid therapy for chronic pain in the United States: Promises and perils. Pain 2013; 154: 94–S100. 

Common opioid side effects

• 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

• 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

• 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.