Opioids for long term pain

The effectiveness of opioids for long term pain

Clinical evidence regarding the effectiveness of opioids for long term pain is unclear. Indeed, there is insufficient evidence to determine the long-term benefits of opioid therapy for chronic pain and there is an increased risk of harms with long-term opioid therapy. This is partly due to few placebo-controlled trials investigating opioid therapy in medium- (6 to <12 months) and long-term (≥ 12 months) time-frames. A 12 month follow up study comparing opioid to non-opioid drugs in patients with chronic back pain or knee and hip pain showed no difference in improving pain related function.¹Regarding the short-term effectiveness of opioids for chronic pain (1 to <6 months), there is some tentative evidence to suggest that opioids may have small improvements in pain intensity, but these may be dependent on a number of factors e.g., chronic pain condition and co-morbidities of the patient.

It is also important to keep in mind that patients participating in these randomised controlled trials have been selected based on strict inclusion and exclusion criteria, 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 in usual clinical practice and dose titration is closely supervised. As a result, it is challenging to generalise the findings from these randomised controlled trials to everyday clinical practice. Although this may indicate the need for case series and open-label research, data from research using these designs does not enable firm conclusions regarding improvement in pain intensity, function or quality of life due to the influence of confounding variables and the inability to infer causality between opioids and reported outcomes.

Taken together, this means that non-pharmacologic and non-opioid treatments should be optimised first as appropriate for the specific condition and the patient considering the biopsychosocial aspects of the patient’s pain (e.g., exercise, physiotherapy, psychological therapies, acupuncture). Initiating a trial of opioid therapy should only be considered if established non-pharmacologic and non-opioid treatments are not effective, not tolerated, contraindicated and/or not available, and if expected benefits for pain and function are anticipated to outweigh the associated risks to the patient. Given the harms associated with opioid treatment and the probability of therapeutic disappointment in the long term, exploration of opioid therapy for a patient with long-term pain should be carefully planned and closely monitored. This should include clinicians having a discussion with the patient of the realistic benefits and known risks of opioid therapy, working with patients to establish treatment goals for pain and function and how these goals will be evaluated, monitored and documented, and identifying next steps if the opioid therapy is discontinued due to the benefits not outweighing the risks. 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:

Important Practice Points
Always consider broad dose guidance and the value of specialist input Patients who do not achieve useful pain relief or improved function from opioids within 4 weeks are unlikely to gain benefit in the long term. There should be an exit strategy; jointly decided between the clinician and patient at the outset if the opioid therapy is unsuccessful in improving pain and function. Patients who may benefit from opioids in the long term will demonstrate a favourable response within 4 weeks. However, see point 4. Short-term efficacy does not guarantee long-term efficacy. Outcomes should therefore be regularly evaluated and documented by both the patient and clinician. An optimal dose is reached when there has been a demonstrable improvement in pain or function, and further increases have not further improved these. Dose increases after a period of stability, or when a high dose has already been reached without significant benefit, need to be considered carefully and are usually not indicated. Exceptions may include a new acute pain problems for which a temporary increase may be trialled. If the benefits of increasing the dose are considered to outweigh the risks, clinicians should work closely with patients to devise a plan for increasing the dose in a stepwise manner to reach the therapeutic goals, and, in the case of an acute pain for a reduction when the acute issue has resolved.

Important Practice Points

Always consider broad dose guidance and the value of specialist input

Patients who do not achieve useful pain relief or improved function from opioids within 4 weeks are unlikely to gain benefit in the long term.
There should be an exit strategy; jointly decided between the clinician and patient at the outset if the opioid therapy is unsuccessful in improving pain and function.
Patients who may benefit from opioids in the long term will demonstrate a favourable response within 4 weeks. However, see point 4.
Short-term efficacy does not guarantee long-term efficacy. Outcomes should therefore be regularly evaluated and documented by both the patient and clinician.
An optimal dose is reached when there has been a demonstrable improvement in pain or function, and further increases have not further improved these.
Dose increases after a period of stability, or when a high dose has already been reached without significant benefit, need to be considered carefully and are usually not indicated. Exceptions may include a new acute pain problems for which a temporary increase may be trialled.
If the benefits of increasing the dose are considered to outweigh the risks, clinicians should work closely with patients to devise a plan for increasing the dose in a stepwise manner to reach the therapeutic goals, and, in the case of an acute pain for a reduction when the acute issue has resolved.

Side effects of opioids

Side effects are extremely common with opioid therapy and frequently lead to discontinuation.² It is therefore important to set the expectations of patients. Indeed, before the first prescription, opioid-associated side effects should be anticipated and appropriate counselling about common side effects and their management should be provided to patients. Furthermore, 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. Inadequate management of side effects and consequences of opioid treatment may contribute to unplanned hospital admissions and contribute to the overall costs associated with opioid treatment. There is little evidence that, in equianalgesic 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.

Management of opioid related side effects

The most common side effects are predictable consequences of opioid pharmacological actions and include:

Constipation. 60%–80% of patients on opioid therapy have gut-related side effects. Constipation is the predominant complaint, but nausea (see below), vomiting (see below), abdominal pain, and distension are also frequently observed.³Straining, gas production, hard consistency of stools and abdominal discomfort should be considered (as well as number of bowel movements). Gastrointestinal side effects do not tend to improve after initiation of treatment or following an intended dose increase and may require long-term management. Where appropriate, treatments for gastrointestinal side effects should be considered:
1. A small supply of an anti-emetic (e.g., cyclizine, prochlorperazine) may be beneficial when providing the initial prescription of an opioid.
2. Encouraging the patient to drink lots of fluid, and to eat additional fruit and fibre may minimise constipation. However, a combination of stool softener (e.g., docusate sodium) and a stimulant laxative (e.g., senna or bisacodyl) may be necessary.
3. Peripherally acting mu opioid antagonists (such as oral Naldemedine) is recommended for constipation when laxative treatment is not effective.
Nausea and vomiting. Opioid-induced nausea and vomiting are experienced by up to 40% of pain patients with no history of emesis. However, as opioid-induced nausea and vomiting are inconsistent consequences of opioid therapy, prophylactic antiemetics are generally not prescribed. In most patients, tolerance to the emetic effect of opioids develops after 2–4 weeks. Routine administration of antiemetics is therefore not necessary.⁴
Pruritus. Opioids are considered the best-known medicine to evoke pruritus.⁵ Pruritus tends to persist throughout treatment and may require long-term management. Several treatment options have been tested for opioid-induced pruritus, but none have been found fully satisfactory.⁵ A reduction in opioid dose or switching to another opioid should therefore be considered if opioid-induced pruritus occurs ⁴.
Dizziness and sedation. Central side effects, such as dizziness and drowsiness, 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. If these effects persist, dosages should be considered for reduction or consideration should be made to switch to another opioid. ⁴
Cognition: Opioids can cause reduction in memory, concentration and difficulty in processing information. If this does happen, opioid dose should be considered for reduction or stopped.
Myoclonic movements. Myoclonus can occur in patients on chronic opioid therapy ⁶at very high doses and is very rare. If this does happen, opioid doses should be considered for reduction or consideration made to switch to another opioid.⁴
Increase in pain severity. For some patients in opioid therapy, their pain severity may increase. It is important to ascertain why this occurs through close monitoring of dose reduction. There are a number of reasons why a patients may report an increase pain intensity:
1. Tolerance. After ongoing exposure to opioid therapy, some patients may develop tolerance (the same dose of drug produces less analgesic effect over time).
2. Disease progression. In some chronic pain conditions, the symptoms can deteriorate as a result of progression of the syndrome.
3. Opioid-induced hyperalgesia. This is characterised by a worsening of symptoms despite an increase in opioid dose.
Dry mouth. Opioids can cause dry mouth as a result of affecting the production of saliva. This tends improve shortly after initiation of treatment or following an intended dose increase.
Urinary retention. Opioids can be associated with urinary retention, particularly in elderly patients due to existing comorbidities.⁷ If this occurs, a reduction in opioid dose or a switch to another opioid should be considered.⁴

Harmful side effects

Respiratory-related:
- 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 chronic 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 e.g., continuous positive airway pressure. Patients with sleep apnoea being prescribed opioids will need regular and detailed assessment of treatment.
- Opioids should only be started in patients with sleep-related breathing disorders after very carefully balancing potential benefits and risks. Opioid treatment should be considered for discontinuation if sleep-disordered breathing occurs and does not improve despite optimisation of breathing therapy and/or reduction or cessation of other medications which negatively affect respiration (hypnotics, antipsychotics).⁴
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.
Hypogonadism. Long-term opioid therapy can lead to hypogonadism which is characterised by sexual dysfunction and infertility. The management of hypogonadism can include a reduction in opioid dose, opioid rotation and hormone replacement.⁴
Falls and fractures. Opioid use increases the risk of falls and fractures.^{2, 8}
Cardiovascular events. Although there is limited research into the cardiovascular events associated with long-term opioid use, preliminary evidence has identified an associated between long-term opioid use for chronic pain and an increased risk of myocardial infarction.²
Opioid use disorder and dependence. Long-term opioid use has been associated with a significantly increased risk of abuse or dependence for all doses of opioids.² It is thought that any current or previous substance use, any mental health diagnosis, younger age and male sex are predictors of the development of misuse among patients with outpatient opioid prescriptions.⁹ If opioid use disorder is suspected, clinicians should discuss their concern with their patient in a non-judgmental manner and provide an opportunity for the patient to disclose related concerns or problems. Collaboration with an opioid use disorder treatment specialist should be considered for the management of opioid use disorder. Treatment options could include opioid tapering, continuation of therapy with a stable opioid dose, psychological therapies and buprenorphine or methadone therapy.⁴
Long term opioid use is associated with adrenal insufficiency.^{10, 11}
Overdose. Observational studies in North America have reported important risks of non-fatal and fatal unintentional overdose from long-term opioid use. This is contrast to the low rates reported in randomised controlled trials and may be due to strict inclusion and exclusion criteria, close monitoring of patients, short follow up duration and non-systematic assessment of opioid use disorder or dependence. Nevertheless, overdose is a serious side effect of opioid therapy, particularly in long-term opioid therapy. To reduce the risk of overdose, patients should be educated on overdose prevention, including when opioids are combined with other drugs or alcohol, naloxone use and be monitored frequently. For patients who have a non-fatal overdose, they should be evaluated for opioid use disorder and/or dependence and have appropriate treatment.¹²

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.

References:

1. Krebs EE, Gravely A, Nugent S, et al. Effect of Opioid vs Nonopioid Medications on Pain-Related Function in Patients with Chronic Back Pain or Hip or Knee Osteoarthritis Pain: The SPACE Randomized Clinical Trial. JAMA. 2018;319(9):872–882. doi:10.1001/jama.2018.0899

2. Chou R, Hartung D, Turner J, et al. Opioid Treatments for Chronic Pain [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2020 Apr. (Comparative Effectiveness Review, No. 229.).

3. Farmer AD, Drewes AM, Chiarioni G, De Giorgio R, O’Brien T, Morlion B, Tack J. Pathophysiology and management of opioid-induced constipation: European expert consensus statement. United European Gastroenterol J. 2019 Feb;7(1):7-20.

4. Krčevski Škvarč, N, Morlion, B, Vowles, KE, et al. European clinical practice recommendations on opioids for chronic noncancer pain – Part 2: Special situations. Eur J Pain. 2021; 25: 969–985.

5. Reich A, Szepietowski JC. Opioid-induced pruritus: an update. Clin Exp Dermatol. 2010 Jan;35(1):2-6. Doi: 10.1111/j.1365-2230.2009.03463.x. Epub 2009 Jul 29. PMID: 19663845.

6. Yamamoto Y, Watanabe H, Watanabe N, et al. Frequency of Myoclonus and its Countermeasures in Terminally Ill Patients with Cancer: A Single-Center Retrospective Study. J Pain Pall Care Pharmacother. . 2024;38(2):117-122. doi:10.1080/15360288.2024.2345326

7. Verhamme KM, Sturkenboom MC, Stricker BH, Bosch R. Drug-induced urinary retention: incidence, management and prevention. Drug Saf. 2008;31(5):373-88.

8. NICE. Falls in older people: assessing risk and prevention. CG161. https://www.nice.org.uk/guidance/cg161/resources/falls-in-older-people-…. Published 2013. Accessed.

9. Cragg A, Hau JP, Woo SA, Kitchen SA, Liu C, Doyle-Waters MM, Hohl CM. Risk Factors for Misuse of Prescribed Opioids: A Systematic Review and Meta-Analysis. Ann Emerg Med. 2019 Nov;74(5):634-646.

10. Li, Taoran, et al. "Prevalence of opioid-induced adrenal insufficiency in patients taking chronic opioids." The Journal of Clinical Endocrinology & Metabolism 105.10 (2020): e3766-e3775.

11. Donegan, Diane, and Irina Bancos. "Opioid-induced adrenal insufficiency." Mayo Clinic Proceedings. Vol. 93. No. 7. Elsevier, 2018.

12. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical Practice Guideline for Prescribing Opioids for Pain — United States, 2022. MMWR Recomm Rep 2022;71(No. RR-3):1–95.

13. NICE. Naldemedine for treating opioid-induced constipation. TA651.https://www.nice.org.uk/guidance/ta651

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