Background   Relief of cancer pain from opioids is rarely all or nothing; most patients experience some degree of analgesia alongside opioid toxicities and residual pain. When the balance of analgesia versus toxicity tips away from analgesia, the term ‘opioid poorly responsive pain’ is invoked. While opioid poorly responsive pain is not a discreet syndrome, it is a commonly encountered clinical scenario. This Fast Fact reviews key points in its assessment and management.

Differential diagnosis of opioid poorly responsive pain 

1. Cancer-related pain.
   1. Cancer progression (new fracture at site of known bone metastases).
   2. Causes of pain (e.g. neuropathic pain, skin ulceration, rectal tenesmus, muscle pain) that are known to be less responsive to systemic opioids or opioid monotherapy.
   3. Psychological/spiritual pain related to the cancer experience (existential pain of impending death).
2. Opioid pharmacology/technical problems.
   1. Opioid tolerance (rapid dose escalation with no analgesic effect).
   2. Dose-limiting opioid toxicity (sedation, delirium, hyperalgesia, nausea – see Fast Fact #25 and Fast Fact #142).
   3. Poor oral absorption (for PO meds) or skin absorption (e.g. transdermal patch adhesive failure).
   4. Pump, needle, or catheter problems (IV, subcutaneous, or spinal opioids).
3. Non-cancer pain.
   1. Worsening of a known non-cancer pain syndrome (e.g., non-malignant spondylosis).
   2. New non-cancer pain syndrome (dental abscess).
4. Other psychological problems.
   1. Depression, anxiety, somatization, hypochondria, factitious disorders.
   2. Dementia and delirium both effect a patient’s report of and experience of pain.
   3. Opioid use disorders or opioid diversion.

Management Strategy 

1. Initial Steps
   1. Complete a thorough pain assessment including questions exploring psychological and spiritual concerns. If opioid use disorder or diversion is suspected, complete a substance abuse history (see Fast Fact #68 and Fast Fact #69).
   2. Complete a physical examination and order diagnostic studies as indicated.
   3. Treat opioid toxicities aggressively.
   4. Use (start or up-titrate) adjuvant analgesics, especially for neuropathic pain syndromes.
   5. Integrate non-pharmacological treatments such as behavioral therapies, physical modalities like heat and cold, and music and other relaxation-based therapies – see Fast Fact #211.
   6. If you have done the above steps, consider whether you should escalate a single opioid until acceptable analgesia or unacceptable toxicity develop. Sometimes it is clear that additional analgesic benefit is not being derived from opioid dose escalation. If this occurs, consider:  
      1. Rotating to a different opioid (e.g. morphine to methadone).
      2. Changing the route of administration (e.g. oral to subcutaneous).
2. Additional steps – Pain refractory to the initial steps requires multi-disciplinary input and care coordination. Consider the following:
   1. Hospice, palliative medicine, or pain management consultation to optimize pain assessment, drug management, and assessment of overall care goals.
   2. Mental health consultation for help in diagnosis and management of suspected psychological factors contributing to pain.
   3. Chaplain/clergy assistance for suspected spiritual factors contributing to pain.
   4. Interventional radiology consultation.
   5. Radiation oncology consultation.
   6. Rehabilitation consultations (PM&R, physical and occupational therapy) to maximize physical analgesic modalities.
   7. Pharmacist assistance with drug/route information.

References 

1. Mercadante F, Portenoy RK. Opiate Poorly Responsive Cancer Pain Parts 1-3. J Pain Symptom Management. 2001; 21(2):144-150, 21(3):255-264, 24(4):338-354.
2. Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002; 20(19):4040-9.
3. Fallon M. When morphine does not work. Support Care Cancer. 2008; 16(7):771-5.
4. Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database of Systematic Reviews. 2004, Issue 3. Art. No.: CD004847. DOI: 10.1002/14651858.CD004847.
5. Hanks GW.  Opioid-responsive and opioid-non-responsive pain in cancer. Br Med Bull. 1991; 47(3):718-31.
6. Hanks G, Forbes K. Opioid responsiveness.  Acta Anaesthesiologica Scand.1997; 41:154-158.

Author Affiliations:  University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania (TS, RA), and Medical College of Wisconsin, Milwaukee, Wisconsin (DEW).   
Version History:  Originally published May 2009; copy-edited August 2015; then again February 2025. 
Conflicts of Interest: None to report.