Opioid-Induced Hyperalgesia: Overview and Management Approach

In this month’s Palliative Pearls Case Study, we meet a patient with stage IV colon cancer with no significant past medical history. Despite increasing continuous morphine dosing by 400% and using 75% of available bolus doses, KD’s pain is getting worse. Even her bed sheets are causing her pain. She is irritable and agitated, unable to have meaningful interaction with her husband and children. Clinicians suspect Opioid-induced hyperalgesia. How can they best treat this cancer patient’s pain without neurotoxic side effects?  Download this month’s case study to share with your colleagues or continue reading below.


KD is a 48-year-old female patient with stage IV colon cancer with no significant past medical history. With the support of her family, KD elected to enroll in hospice after several unsuccessful trials of chemotherapy and radiation. She resides at home with her husband and two young children with the main goal of remaining comfortable enough to interact with them.

Current Medications:

  • Gabapentin (Neurontin®) 600mg; 1 capsule by mouth 3 times daily for nerve pain
  • Morphine infusion; infuse IV @ 20mg/hr with a 5mg bolus every 15 minutes as needed for pain
  • Lorazepam (Ativan®) 1mg; 1 tablet by mouth every 6 hours for anxiety
  • Haloperidol (Haldol®) 5mg; 1 tablet by mouth every 6 hours as needed for agitation
  • Temazepam (Restoril®) 30mg; 1 capsule by mouth at bedtime for sleep
  • Polyethylene glycol (Miralax®); mix 1 capful (17gm) in 8 ounces of water and drink daily to prevent constipation
  • Metoclopramide (Reglan®) 10mg; 1 tablet by mouth before meals for nausea/vomiting
  • Ondansetron (Zofran®) 8mg; 1 tablet by mouth every 8 hours as needed for nausea/vomiting

KD was discharged from the hospital to hospice services at home 14 days ago on a morphine continuous infusion. Following continued reports of unrelieved abdominal pain and a dull aching pain in her hip and back, the infusion rate was titrated from 5mg/hr to her current rate of 20mg/hr. The bolus dose was increased from 2mg to 5mg. Despite rate titration and the use of 75% (72 doses) of the available bolus doses in 24 hours, KD has escalating pain, now reporting the bed sheets laying across her legs results in pain. KD is irritable and agitated, unable to have meaningful interaction with her husband and children.


Common opioid side effects are expected and include nausea, constipation, and itching. Neurotoxic side effects may not be as familiar or common but still important to recognize. Opioid-induced hyperalgesia (OIH) is just one of a handful of neurotoxic effects that also include myoclonus (muscle twitching or jerking), delirium, and hallucinations.1

OIH is a phenomenon that results in worsening pain despite an increase in the total daily opioid dose.2 While there are several proposed mechanisms, the source remains unknown despite reports in the literature dating back to 1870.3 OIH is more prevalent with chronic use of high-dose opioids, but has also been reported in post-surgical patients who were administered opioids acutely, particularly at higher doses.3 Patients with renal failure are also at increased risk for OIH due to accumulation of metabolites.2

In the hospice and palliative patient population, pain management employing opioids is common for managing severe and chronic pain. With many patients requiring escalating opioid doses, it’s important to be familiar with clinical features of this OIH including:2

  • Elevation of pain despite increased opioid use
  • Pain that seems to be spreading over a larger area
  • Increased response to pain, especially to stimuli not typically painful (e.g., clothing, sheets)


When OIH is suspected, there are several management approaches found beneficial:2-4

  • Opioid rotation – Initiate a dissimilar opioid at a reduced dose, preferably one with less potential of metabolite accumulation resulting in neurotoxic effects (e.g., fentanyl or methadone)
  • Adding non-opioid adjuvant therapy – Utilize medications targeting different pain pathways. This can result in an opioid-sparing effect which would grant better pain control, potentially decreasing the opioid requirement.
  • Dose reduction of current opioid – It is theorized that neurotoxic effects exhibit themselves once a metabolite threshold is exceeded. Reducing the total daily dose of the current opioid may resolve this and begin to alleviate pain.

Studies have shown benefit in converting patients experiencing OIH to methadone.3 Consider patient prognosis in week(s) and potential drug-drug and drug-disease interactions before initiating methadone. If the patient has time to benefit (prognosis >1 week) and no significant drug-related interactions, methadone is a preferred option for several reasons. Methadone manages pain via a different pathway than other opioids by antagonizing the NMDA receptor and is safe to use in patients with renal impairment since it has no active metabolites.3,5

Regardless of the approach taken, the communication between the patient/family and the care team is vital to prevent confusion and manage expectations.3,5 Any approach requires caregiver trust and communication with assurance that the chosen path is likely to make the patient most comfortable.


OIH is suspected based on KDs report that pain is intensifying despite an increase in opioid usage with pain elicited from the normally non-painful stimulus of her sheets. With a predicted prognosis of 4-6 weeks and no significant drug interactions noted, the decision is made to convert to methadone.5


  1. Initiate scheduled doses of methadone at 10mg by mouth every 8 hours using the “stop and go” method:5
    • The methadone dose was based on 2,520mg OME (oral morphine equivalent). Using a 20:1 dosing conversion, the total daily dose of methadone calculated was 126mg.6 Despite the total daily dose of previous opioid, consensus guidelines recommend against initiating methadone at a dose greater than 30-40mg a day.6 It was thus determined to begin methadone 10mg by mouth every 8 hours.
    • Stop the morphine continuous infusion with the start of scheduled methadone.
    • Continuing with the morphine bolus of 5mg IV every 15 minutes as needed for breakthrough needs for the next 7 days.5
  2. Initiate dexamethasone 4mg by mouth twice daily for suspected bone metastases.
  3. Discontinue the “as needed” haloperidol due to non-use and concern for potential drug-drug interaction with methadone.
  4. Monitor daily for pain management and side effects.
  5. On day 7, reassess pain and bolus use; adjust methadone and bolus dose accordingly.
  6. Consider discontinuing the morphine IV bolus and convert to oral morphine for breakthrough needs.

As the week progressed after initiating the methadone and dexamethasone, the patient appeared more comfortable and was covered with a blanket. KD reported that her pain relief was the best it has been in weeks and with each day she found herself requiring fewer bolus doses. On day 8, it was determined that she was on an appropriate dose of methadone and was transitioned over to oral morphine for breakthrough pain. With increased comfort, the patient was able to spend more time with her children and passed away peacefully 4 weeks later.


  1. Wilson RK, Weissman DE. Fast Facts and Concepts #57: Neuroexcitatory effects of opioids –patient assessment. Updated May 2015. Article link
  2. Teuteberg WG. Fast Facts and Concepts #142: Opioid-induced Hyperalgesia. Updated July 2015. Article link
  3. Yi P, Pryzbylkowski P. Opioid Induced Hyperalgesia. Pain Medicine (Malden, Mass.) [serial online]. October 2015;16 Suppl 1:S32-S36. Available from: MEDLINE, Ipswich, MA.
  4. Wilson RK, Weissman DE. Fast Facts and Concepts #58: Neuroexcitatory effects of opioids. Updated May 2015. Article link
  5. McPherson ML. Chapter 6: Methadone – A Complex and Challenging Analgesic, But It’s Worth It! In: Demystifying Opioid Conversion Calculations, A Guide to Effective Dosing, 2nd edition. Bethesda, MD: American Society of Health-System Pharmacists, Inc; 2018.
  6. McPherson ML, Walker KA, Davis MP, et al. Safe and Appropriate Use of Methadone in Hospice and Palliative Care: Expert Consensus White Paper. J Pain Symptom Manage 2019;57:635-645.
  7. Bannister K. Opioid-induced hyperalgesia: Where are we now? Current Opinion In: Supportive and Palliative Care [serial online]. June 2015;9(2):116-121. Available from: MEDLINE, Ipswich, MA.
  8. Gazelle F, Fine PG. Fast Facts and Concepts #75: Methadone for the Treatment of Pain. Updated June 2015. Article link
  9. Dalton, C. (2018). National Public Radio. When Opioids Make Pain Worse. Article link