Clinician and clinical research perspectives on opioid analgesic tolerance and hyperalgesia

Michael C. Rowbotham, MD Chief Research Officer, Sutter Health Adjunct Professor of Anesthesia, Emeritus Professor of Neurology, UCSF Attending Neurologist, UCSF Pain Management Center

Day 1, Session 1: Clinical need and risks associated with higher daily dose and higher dosage strength opioid analgesics: Clinician and patient perspectives

1 Relevant experience 1979-80 Fellowship UCSF Drug Dependence Research Lab

1982-84 Medical Director, SFGH/UCSF Substance Abuse Services (Methadone detox and methadone maintenance clinics)

1986-88 Pain Research Fellowship with Howard Fields at UCSF

1989-on UCSF Pain Management Center Attending Neurologist (Associate Director 1989-2009)

1989-09 Founder and Director, UCSF Pain Clinical Research Center First placebo controlled i.v. opioid trial for neuropathic pain 1991 Opioid 8 week trial for neuropathic pain 2003 Opioid 6 month trial for chronic pain hyperalgesia pain models 2006

2009-18 Scientific Director, CPMC Research Institute (Sutter Health)

2018-on Chief Research Officer, Sutter Health 2 Can opioid therapy make pain worse? 19th century perspective

“Pain, which I know is an evil, is less injurious than morphia, which may be an evil.” “Does morphia tend to encourage the very pain it pretends to relieve?”

Albutt C. On the abuse of hypodermic injections of morphia. Practitioner 1870; 5:327-331.

3 The current opioid epidemic is at least 18 years old

2001 2003

4 Faced with an opioid epidemic of abuse, addiction, and death, “the pendulum swings from pain control to drug control” [Goesling 2019]

5 Opioids are effective but…..

 Opioids – effective compared to placebo, antidepressants, and anticonvulsants (Busse et al, JAMA 2018)  CAVEATS:  Little efficacy data spanning over long time periods (6 months +) for opioids or any drug class  Drop out rates in trials of opioids higher than for non- opioids  Many patients cannot tolerate mood and other effects  Stigma and fear of addiction leads to self-dc  Prescribers fear licensing board investigation and reputational damage

6 Physicians are a big part of the problem

Exposure to prescription opioids increases risk for opioid abuse, overdose, and other adverse events in a dose- and duration-dependent manner

 Prescribers are, directly or indirectly, the source of most misused opioids. Opioid prescribing often continues after abuse is diagnosed.

 Opioid dose predicts overdose risk. Decreasing prescribed opioid doses not yet proven to reduce risks to patients.

 Opioids plus benzodiazepines/sedatives or alcohol: 80% of unintentional opioid overdose deaths may involve benzodiazepines.

 Urine testing under-utilized. Requiring very frequent office visits before refilling Rx is both legal and ethical.

7 Why is it so hard to demonstrate long-term opioid efficacy?

 Placebo response doesn’t stabilize - increases over duration of study  Confounds demonstrating long-term efficacy of any drug for pain

Quessy and Rowbotham 2008 8 Tolerance

Dose escalation or loss of analgesic efficacy during longer term treatment of chronic non-malignant pain

9 Analgesic tolerance during brief morphine therapy Double-blind, placebo controlled RCT in healthy volunteers

Petersen, Rowbotham, et al, PAIN 2008 10 Analgesic tolerance during brief morphine therapy Double-blind, placebo controlled, parallel group RCT in healthy volunteers

N= 52 p= 0.06 Petersen, Rowbotham, et al, PAIN 2008 No hyperalgesia or withdrawal 11 Dose escalation and analgesic efficacy during longer term therapy

Chronic non-malignant pain

12 Daily morphine for chronic musculoskeletal pain

9 Morphine Placebo

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Placebo Mean PainIntensity 6 Morphine Wash- Wash- Titration Evaluation out Titration Evaluation out 5 3 weeks 6 weeks 2 weeks

Moulin et al. Lancet. 1996;347:143-147 13 Levorphanol for Peripheral and Central Neuropathic Pain: Low- vs High-Strength Levorphanol Capsules Randomized, Double-Blind Comparison

Baseline Tapering Tapering Tapering Tapering Screening Week Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 1 Week 2 Week 3 Week 4

Maximum,Maximum, Maximum, Maximum, 3 9 15 21 capsules capsules capsules capsules

Titration Treatment Tapering (maximum, (up to 4 weeks) 21 capsules) No opioids allowed

Rowbotham et al. N Engl J Med. 2003;348:1223-1232 14 No. at risk risk at No. 15 Intensify of Pain Category of on Visual Analogue No. of Pain Relief Scale (mm) Capsules/Day 100 20 40 60 80 12 15 18 21 0 1 2 3 4 5 0 3 6 9 0 Baseline 81 P 1 P group High =.02 <.001 2 WeekTreatment of WeekTreatment of WeekTreatment of 81 1 - 2 strength 80 2 3 High 4 Low 77 Low High 3 - - 4 strength group strength group - - strength group 70 strength group 4 5 Low group 67 6 5 - strength 60 6 6 60 7 8 7 59 8 8 B A C A Closer Look… A Closer ratings relief in difference group significant No relief pain and reduction, pain intake, capsule in early behind fell drops Eventual group strength - high in to due agitation AEs; drops 15 completed subjects randomized,81 59 Maximal Daily Dose of Levorphanol (mg/day) 10 12 13 14 15 16 11 0 1 2 3 4 5 6 7 8 9 Group High-Strength highly variable dose dailyActual Group Low- Strength Opioid-Induced Hyperalgesia (OIH)

 State of nociceptive sensitization caused by exposure to opioids  Frequently invoked as major contributor to addiction, dose escalation, and overdose  Historical data anecdotal, confounded  Opioid tx chronic pain & methadone maintenance cold sensitivity  In humans, little or no prospective data to support OIH  Chu 2012 found tolerance but not cold hyperalgesia after 1 month  Rowbotham and Wallace data

16 Study Design stable non-cancer pain no history of opioid abuse no current or recent drug/alcohol abuse cooperative primary physician

Naïve High dose Low dose Titration Dose FIXED Taper (5 weeks) (1-4 weeks) Maintained (20 weeks) High dose Low dose

BTS pain model testing

UCSF-UCSD collaboration: Rowbotham, Petersen, Wallace Opioid-naïve = <30 mg/day MS Opioid-maintained = 30-150 mg/day MS 17 Initiation to end of stable treatment (Day 147): 17/30 subjects completed BTS Area mm2

Pain Prior V2 V4 V5 V7 V9 week

Pain now

Visit number Final opioid dose avg 138 MEQ Range 14-300 MEQ/day 18 • possible OIH in 3/17 completers: • Deterioration in daily pain scores = clinical deterioration. • At V7 - enlargement in post-dosing BTS area and increased painfulness of heating = hyperalgesia. • If the perceived analgesic effect at an observed dosing session (% pain relief at 90 minutes) was also reduced compared to the end of titration, it would constitute evidence of both tolerance and hyperalgesia.

19 5 takeaways

 Who should receive opioids? Chronic pain patients treated with opioids are not that different from methadone maintenance patients

 The hardest part of tapering off opioids for patients is starting; a complete taper is often an unrealistic goal

 Clinicians struggle to set limits and monitor patients closely; slow to recognize dependence and abuse, toxic combinations of opioids and sedatives/alcohol

 What is opioid analgesic tolerance? When does it start?

 What is opioid-induced hyperalgesia?

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