Opioid Tolerance, Hyperalgesia Increase Following Stable Dosing

Michael Rowbotham, MD

Opioid analgesic tolerance and opioid-induced hyperalgesia appeared in several patients during a period of stable opioid dosing, according to recent findings.

Michael Rowbotham, MD, and a team of investigators designed a randomized, double-blind, parallel dose-response to determine if after 5 weeks titration, opioid analgesic tolerance and opioid-induced hyperalgesia emerged during 20 weeks of stable dosing.

The team found that 18% of patients had evidence of both tolerance and opioid-induced hyperalgesia.

Rowbotham, from the California Pacific Medical Center Research Institute, and colleagues used data from patients who attended <12 visits at the University of California San Francisco Pain Clinical Research Center or the University of California San Diego Center for Pain Medicine over 30 weeks. The team included 30 stable chronic non-malignant patients for a six-month long trial of the opioid levorphanol. Overall, 11 were taking no opioids at study entry and 11 were taking between 35-122 morphine equivalents.

The study had 4 periods: screening (1-2 weeks); dose titration (5 weeks); stable dosing (20 weeks); and levorphanol taper (1-4 weeks).

After patients were screened, those eligible were randomized by the research pharmacist to receive identical-appearing low or high strength capsules of levorphanol. Eligible patients had moderate to severe chronic nonmalignant pain and either wanted to try opioid therapy or opioid dose escalation. Randomization was stratified based on the patient’s pre-study opioid use as “opioid-naïve” or “opioid-maintained.”

The five-week titration period began at visit 2 and patients received their first dose under direct observation for >120 minutes after dosing. Patients added capsules dispensed by the research site to determine the totally daily dose that they felt provided the best balance between pain relief and side effects.

Following the titration period, the maximum total daily dose was fixed for the 20-week stable dosing period. During this time, patients could decrease levorphanol intake as needed to manage their side effects. A tapering period of 1-4 weeks came after.

At each visit, patients completed questionnaires, had their vital signs checked, completed an adverse event assessment, and reviewed pain diaries and medication use. Patients determined their tolerance and opioid-induced hyperalgesia based on chronic pain ratings, Brief Pain Inventory scores, and results of the Brief Thermal Sensitization model at 5 opioid dosing sessions.

The investigators assessed the effect of opioid administration on acute experimental and chronic clinical pain at 5 of the 12 visits. At those visits, participants underwent the brief thermal sensitization model before and 90 minutes after taking the opioid dose, which was a third of their scheduled daily total intake. The brief thermal sensitization model had a quantitative endpoint of hyperalgesia area and repeated ratings of stimulus pain during heat application.

The primary outcome of the pain model related measures was the size of area of secondary hyperalgesia to von Frey hair stimulation after the brief thermal sensitization.

The main pain outcome was the self-rating of pain during the past week. Secondary measures included 0-100 visual analog scale ratings of the severity of chronic pain “right now” that were collected at the lab during the dosing session, the estimate of the percent relief “right now,” the Patient Global Impression of Change, and the mean of the 7 Modified Brief Pain Inventory interference scores.

Opioid analgesic tolerance was present if the individual patient’s rating of pain during the past week increased during the stable dosing period (visits 9-10) compared to the end of titration (visits 4-5) or at the beginning of the study (visit 2). Deterioration in the Patient Global Impression of Change or Modified Brief Pain Inventory ratings and less pain reduction during the 90-minute observed administration period.

Opioid-induced hyperalgesia was present if a patient had an increase across the pain model visits from the pre- and post-dose values collected at the second visit for the brief thermal sensitization area and the post-dose painfulness of the stimulation.

Overall, 20 women and 10 men with an average age of 50.8 years old (range 21-76 years old) participated. The patients suffered from chronic lower back pain (12); focal nerve injury (3); fibromyalgia (3); rheumatoid arthritis (2); osteoarthritis (2); chronic neck pain (2); neuropathic cranial pain (1); postherpetic neuralgia pain (1); peripheral neuropathy (1); neurofibromatosis (1); complex regional pain syndrome 1 (1); and central pain from cervical myelopathy (1).

Just 2 patients had pain for <1 year, while 22 had pain for >5 years.

The average pain during visits 1-2 based on their ratings of pain during the past week was 63.7 and the average pre-study daily opioid use was equivalent to 36.3 mg of morphine per day (range 0-122 mg/day morphine equivalent). Eleven patients were opioid-maintained and 19 were opioid naïve.

Some participants (7) withdrew from the study during the titration period and 6 during stable dosing. Patients reported a change in health and pain not controlled, while 7 of the 11 patients not taking opioids at study entry dropped.

In total, 17 patients attended visit 9 and completed all pain model and observed dosing visits. The average of their visual analog scale ratings of pain during the past week was 63.6/100 for visits 1-2, 47.9 for visits 4-5, and 45 for visits 9-10.

Throughout the titration period, 13 of the 17 patients improved, 3 were unchanged (1 point or less change in the 0-100 visual analog scale), and 1 patient worsened. The average improvement was 25% (range, 96% improved-38% worse).

Over the course of the full study, the average improvement was 23% and the median improvement was 19%.

Of the 4 patients who completed the study and did not take opioid at entry, an average of 64 mg/day morphine equivalent were added and there was a 4% reduction in chronic pain. Among those who took opioids at entry, there was an average of 118 mg/day of added morphine equivalent and an average improvement of 29%.

At visit 2 in all 30 patients prior to opioid dosing, the secondary hyperalgesia area averaged 256 cm² (median 228 cm²; range 49-536 cm²; 95% CI, 210-303 cm²). After the opioid dosing, the secondary hyperalgesia area was almost the same 90 minutes later at 263 cm² (median 241 cm²; range49-552 cm²).

The painfulness of skin heating averaged 42.4 on the 0-100 scale (median 42.8; range 0-81; 95% CI, 32-52) at visit 2, while after dosing, it decreased to 34.2 on the scale.

Reduction of pain was clear at the end of the dose titration phase, but 10 of the 17 patients who completed the study demonstrated opioid analgesic tolerance, meaning they lost all initial benefit by the end of 20 weeks of stable dosing. What’s more, 8 of the 17 patients ended the study with greater pain intensity scores than at entry, which suggested possible tolerance and opioid-induced hyperalgesia.

The findings implied that because the study was conducted during a time of greater permissiveness regarding higher dose opioids, patients could easily exceed current CDC guidelines.

The study, “Evolution of Analgesic Tolerance and Opioid-Induced Hyperalgesia over 6 months: Double-blind randomized trial incorporating experimental pain models,” was published online in The Journal of Pain.