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Date: January 10th , 2019

Reference:  Busse JW et al. Opioids for Chronic Noncancer Pain A Systematic Review and Meta-analysis. JAMA December 2018

Guest Skeptic: Dr. Sergey Motov is an Emergency Physician in the Department of Emergency Medicine, Maimonides Medical Center in New York City. He is also one of the world’s leading researchers on pain management in the emergency department and specifically the use of ketamine. His twitter handle is @PainFreeED.

Case: A 45-year-old woman with chronic low back pain due to L4/5 disk herniation for over one-month presents to the emergency department with chief complaint of worsening left sided back pain over past week after doing some heavy lifting at work. She denies bowel or bladder dysfunctions, weakness in her bilateral lower extremities or loss of sensation in her legs. On physical examination, the patient has no sensory deficits but does have pain upon straight left leg raise at L4-S1 distribution. While you are contemplating therapeutic modalities, the patient tells you that she has been taking oxycodone several times a day and occasionally gabapentin, but the pain does not seem to be getting better. She asks you how much longer she needs to continue taking oxycodone to see some improvement.

Background: Opioids are frequently prescribed for patients with chronic non-cancer (nociceptive and neuropathic) pain, however, the prolonged use of these analgesics may not provide significant pain relief but instead may lead to development of significant adverse effects such as tolerance, dependence, misuse, and in some cases, a development of an opioid use disorder.

Therefore, there is a need for high quality research including systematic reviews that can either support or refute the analgesics efficacy and safety in patients suffering from CNCP.

We haver reviewed papers on pain management in the emergency department for many years on the SGEM. One of the first episodes to look at opioids for pain management was SGEM#55. Our bottom line from that episode was that opioid prescribing in the emergency department will continue to be a problem. The study reviewed does not provide enough high-quality information to implement this guideline at my hospital.

The case scenario for this episode is a woman with worsening low-back pain for a month. Many different pharmaceutical treatments have been tried for acute low back pain with limited success. These include acetaminophen, muscle relaxants, non-steroidal anti-inflammatories (NSAIDs), steroids and benzodiazepines.

  • Acetaminophen: Williams et al (Lancet 2014) showed acetaminophen did not affect recovery time compared with placebo in low-back pain. However, these were not patients recruited from the emergency department.
  • Muscle Relaxants: Friedman et al (JAMA 2015) showed that adding a muscle relaxant (cyclobenzaprine) or oxycodone/acetaminophen to an NSAID (naproxen) alone did not improve functional outcomes or pain one week after emergency department presentation.
  • NSAIDs: Machado et al (Ann Rheum Dis 2017) demonstrated in a SRMA that NSAIDs did not provide clinically important effects over placebo for spine pain. They included patients with acute and chronic lumbar and cervical pain. However, the point estimate for the subgroup analysis of acute low back pain was less than the pre-specified 10 point between-group difference considered clinically significant.
  • Steroids: Balakrishnamoorthy et al (Emerg Med J 2014) did a double-blind trial of adult patients in the emergency department with acute low back pain and radiculopathy. In this study, the patients received either a single dose of 8 mg of IV dexamethasone or normal saline in addition to oxycodone. While the steroid treatment was reported to shorten the emergency department length of stay and decrease pain up to six weeks after discharge the difference was only statistically significant not clinically significant and there was not difference in functional capacity.
  • Benzodiazepines: Friedman et al (Ann Emerg Med 2017) showed that diazepam was no better than placebo when added to naproxen for acute low back pain (SGEM#173).

A number of non-pharmaceutical treatment modalities have also been tried to treat low back pain. These include cognitive behavioral therapy, mindfulness, chiropractic, physical therapy and acupuncture also with limited success.

  • CBT and Mindfulness: Cherkin et al (JAMA 2016) did a randomized control trial in patients with back pain for greater than three months. They were randomized into CBT, mindfulness or usual care. The intervention groups had a greater clinically meaningful improvement (61% CBT, 58% mindfulness vs. 45% for usual care). However, we need to be cautious in interpreting these results because of the potential placebo effect.
  • Chiropractic: Paige et al (JAMA 2017) did a SRMA of spinal manipulative therapy for acute pain. None of the 26 studies included for analysis blinded the providers and only four blinded the patients. The majority of the studies were classified as low quality. Only two studies had a sham comparison group. There was high heterogeneity (i2=67%). While the primary outcome was statistically significant it did not reach clinical significance.
  • Physical Therapy: Paolucci et al (J Pain Research 2018) did a narrative review on different rehabilitative exercise techniques for management of chronic low back pain. All techniques were better than control but no clear superior method was identified. The authors called for more high-quality research on the topic.
  • Acupuncture: Colquhoun and Novella (Anesthesia and Analgesia 2013) There is no high-quality evidence that acupuncture treats any condition and is just a theatrical placebo (SGEM#187 and SGEM#224).

This gets us back to the use of opioids. The American College of Emergency Physicians (ACEP) has a guideline on the use of opioids for adult patients presenting to the emergency department with acute non-cancer pain or an acute exacerbation of chronic non-cancer pain.

  1. In the adult ED patient with noncancer pain for whom opioid prescriptions are considered, what is the utility of state prescription drug monitoring programs in identifying patients who are at high risk for opioid abuse?
    • Level C Recommendation: The use of a state prescription monitoring program may help identify patients who are at high risk for prescription opioid diversion or doctor shopping.
  2. In the adult ED patient with acute low back pain, are prescriptions for opioids more effective during the acute phase than other medications?
    • Level C Recommendation: (1) For the patient being discharged from the ED with acute low back pain, the emergency physician should ascertain whether nonopioid analgesics and nonpharmacologic therapies will be adequate for initial pain management. (2) Given a lack of demonstrated evidence of superior efficacy of either opioid or nonopioid analgesics and the individual and community risks associated with opioid use, misuse, and abuse, opioids should be reserved for more severe pain or pain refractory to other analgesics rather than routinely prescribed.
  3. In the adult ED patient for whom opioid prescription is considered appropriate for treatment of new-onset acute pain, are short-acting schedule II opioids more effective than short-acting schedule III opioids
    • Level B Recommendation: For the short-term relief of acute musculoskeletal pain, emergency physicians may prescribe short-acting opioids such as oxycodone or hydrocodone products while considering the benefits and risks for the individual patient.
    • Level C Recommendation: Research evidence to support superior pain relief for short-acting schedule II over schedule III opioids is inadequate.
  4. In the adult ED patient with an acute exacerbation of noncancer chronic pain, do the benefits of prescribing opioids on discharge from the ED outweigh the potential harms?
    • Level C Recommendations: (1) Physicians should avoid the routine prescribing of outpatient opioids for a patient with an acute exacerbation of chronic noncancer pain seen in the ED. (2) If opioids are prescribed on discharge, the prescription should be for the lowest practical dose for a limited duration (eg, <1 week), and the prescriber should consider the patient’s risk for opioid misuse, abuse, or diversion. (3) the clinician should, if practicable, honor existing patient-physician pain contracts treatment agreements and consider past prescription patterns from information sources such as prescription drug monitoring programs.

One final thing to remember in patients with chronic non-cancer pain is to manage their expectations. Do not set them up for failure. They need to know their pain might not resolve 100% in the emergency department and that most patients will have persistent symptoms with functional impairment for weeks to months (Itz et al 2013 , Donelson et al 2012  and Costa et al 2012).

Clinical Question: Is the use of opioids to treat chronic non-cancer pain associated with greater benefits or harms compared with placebo and alternative analgesics?

Reference: Busse JW et al. Opioids for Chronic Noncancer Pain A Systematic Review and Meta-analysis. JAMA December 2018

  • Population: Adult patients with chronic non-cancer pain who were randomized to an oral or transdermal opioid (pure opioid or a combination product) vs. any non-opioid or placebo control and were enrolled in the studies with follow-up for at least four weeks.
    • Exclusions: Studies in the form of abstract and rarely used interventions (such as oral ketamine, mexiletine, propoxyphene, dextropropoxyphene, fedotozine, and asimadoline) for chronic noncancer pain in North America
  • Intervention: Administration of oral (pure or combination product) and/or transdermal opioids
  • Comparison: Placebo or active non-opioid comparator
  • Outcome:
    • Primary Outcomes:
      1. Pain difference in change of pain score between groups (via 10 cm VAS)
      2. Physical functioning (via 100-point36-item Short Form Survey (SF-36) scale)
      3. Incidence of vomiting
    • Secondary Outcomes:
      1. Emotional functioning (via emotional 100-point SF-36 mental component score)
      2. Role functioning (via 100-pointSF-36 subscale for role limitations due to physical problems)
      3. Social functioning (via 100-point SF-36 subscale for social functioning),
      4. Sleep (via SF-36 sleep quality 100-mm VAS)
      5. Rates of adverse effects

Authors’ Conclusions: “In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.”

Quality Checklistfor Therapeutic Systematic Reviews:

  1. The clinical question is sensible and answerable. Yes
  2. The search for studies was detailed and exhaustive. Yes
  3. The primary studies were of high methodological quality. Yes, for placebo arm. No for the non-opioid analgesics.
  4. The assessment of studies were reproducible. Yes
  5. The outcomes were clinically relevant. Yes
  6. There was low statistical heterogeneity for the primary outcomes. No. The I2 was 70.4% for pain and 65.7% for physical function.
  7. The treatment effect was large enough and precise enough to be clinically significant. No

Key Results: They identified 96 RCTs (n=26,169) with a median age of 58 years and 61% female.

No clinically significant difference in pain, physical functioning or emotional functioning but an increase in vomiting.

  1. High quality randomized trials that compared opioids to placebo demonstrated that:
    • Opioids were associated with pain relief compared with placebo (weighted mean difference, −0.79 cm [95% CI, −0.90 to −0.68 cm] that did not reach the minimally important difference of 1 cm.
    • Opioids were associated with a small improvement in physical functioning compared with placebo, but did not meet the criterion for the minimally important difference (weighted mean difference, 2.04 points [95% CI, 1.41-2.68 points] on the 100-point SF-36 physical component score.
    • Opioids were not significantly associated with emotional functioning compared with placebo (weighted mean difference, 0.14 points [95% CI, −0.58 to 0.86 points] on the 100-point SF-36 mental component score, P = .70).
    • No association of opioids on role functioning compared with placebo (weighted mean difference, 0.87 points [95% CI, −0.54 to 2.28 points] on the 100-point SF-36 subscale for role limitations due to physical problems, P = .23).
    • An association of opioids with improved social functioning compared with placebo but did not meet the minimally important difference criterion (weighted mean difference, 1.58 points [95%CI, 0.45-2.70 points] on the 100-point SF-36 subscale for social functioning).
    • Opioids were associated with a small improvement in sleep quality compared with placebo but did not meet the criterion for the minimally important difference (weighted mean difference, 3.42 mm [95% CI, 1.58-5.26 mm] on the SF-36 sleep quality 100-mm VAS).
    • Opioids were associated with an increased incidence of vomiting; however, this association was less in the 18 enrichment RCTs (5961 patients) compared with placebo (RR, 2.50 [95% CI, 1.89-3.30].
  1. Low-to-moderate quality randomized trials that compared opioids to non-opioids demonstrated:
    • No difference in the association of opioids vs. anti-inflammatory drugs for pain relief (weighted mean difference, −0.60 cm [95% CI, −1.54 to 0.34 cm] on the 10-cm VAS for pain, P = .21); and no difference in physical functioning between opioids and nonsteroidal anti-inflammatory drugs (weighted mean difference,−0.90points [95%CI,−2.69 to 0.89points] on the 100-point SF-36 physical component score).
    • No difference in pain relief between opioids and nortriptyline (weighted mean difference, −0.13 cm [95% CI, −0.99 to 0.74 cm] on the 10-cm VAS for pain, P= .78); and no difference in physical functioning (weighted mean difference, −5.31 points [95% CI, −13.77 to 3.14 points] on the 100-point SF-36 physical component score).
    • Opioids were associated with greater pain relief than anticonvulsants (weighted mean difference, −0.90 cm [95% CI, −1.65 to −0.14 cm] on the 10-cm VAS for pain) but did not reach minimally important difference of 1 cm; and no difference in physical functioning (weighted mean difference, 0.45 points [95% CI, −5.77 to 6.66 points] on the 100-point SF-36 scale.

This was a very impressive and meticulously executed systematic review and meta-analysis emphasizing the lack of analgesic and functional benefits of long-term opioids use for CNCP at the expense of increased risk of adverse effects. Considering the senior author was Dr. Gordon Guyatt and organized out of McMaster University, we would expect nothing less.

  • Five Strengths:
    1. A comprehensive search for eligible randomized control trials in any language.
    2. Data imputation for missing nonsignificant outcomes.
    3. Use of minimally important differences.
    4. Sensitivity analyses that addressed methodological differences, length of follow-up, and reported vs converted change scores.
    5. Large sample size.
  • Five Weaknesses:
    1. Results of the low-to-moderate quality trials comparing opioids to non-opioid analgesics were restricted to treatment lasting one to six months and may not apply to individuals with substance use disorder or other mental illness, to those involved in litigation, or to those receiving disability benefits.
    2. Most eligible trials allowed for post-randomization titration of opioid dose, which precluded between-trial subgroup analyses of higher vs lower doses of opioids.
    3. There were 73 trials (76%) with frequent (≥20%) missing outcome data.
    4. Only 21 of 96 trials addressed mean or median morphine-equivalent doses per day of 90mg or greater.
    5. Only 48 out of 96 trials (50%) adequately concealed allocation.
  • Five Limitations:
    1. Impossible to assess the long-term associations of opioids with chronic non-cancer pain because no trial followed up patients for longer than six months.
    2. None of the included studies provided rates of developing opioid use disorder and only two reported rates of overdose.
    3. Subgroup effects could not be evaluated for opioids vs. active comparators as there were less than two trials in each subgroup.
    4. The modelling of risk difference for achieving the minimally important difference was based on assumptions that could not be directly assessed and might not have been met.
    5. Heterogeneity associated with pooled estimates for pain relief and functional improvement among trials of opioids vs placebo may have reduced evidence quality.

Comment on Authors’ Conclusion Compared to SGEM Conclusion:  We agree with the authors’ conclusion that the opioid use for managing chronic non-cancer is not clinically superior to placebo or non-opioid analgesics with respect to analgesic efficacy, functional restoration and does result in more side-effects.

SGEM Bottom Line: There appears to be no long-term analgesics benefits from prescribing opioids for chronic non-cancer pain (nociceptive and neuropathic). However, their use is associated with increased adverse events.

Case Resolution: The patient was told that continuous use of oxycodone for her lumbar radiculopathy will not alleviate her pain and improve her functional status to the level she is willing to accept, and that she needs to use a combination of non-opioid analgesics and non-pharmacological treatments like physical therapy and graded exercise with a proper follow-up with a spine specialist or pain management specialist.

Dr. Sergey Motov

Clinical Application: Long-term opioids (up to six months) use for chronic non-cancer pain is not associated with significant analgesic and functional benefits in comparison to placebo or non-opioid analgesics. Their use, however, is associated with higher rates of adverse effects. The routine prescribing of opioids in the emergency department for chronic non-cancer pain (nociceptive and neuropathic) should be discouraged.

What Do I Tell My Patient?  I am afraid that taking opioid analgesics (oxycodone, hydrocodone, hydromorphone, tramadol) for your chronic painful condition will result in more harm to you than in alleviating your pain and restrict your functional status. Therefore, I would recommend you not take this medication any longer and instead, consider using a combination of non-opioid analgesics and non-pharmacological treatments.

Keener Kontest: There was no question last week and therefore no winner last week. Listen to the SGEM podcast on iTunes to hear this the new keener question. If you know the answer send an email to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.