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Morphine Induced Hyperalgesia-Is It Real? History Of Morphine As A Pain Medication

Morphine induced hyperalgesia – is it real? Question was unanswered until now. Research paper published by Swartjes M et al in 2012 suggest morphine induced hyperalgesia is real.1

Physicians, law enforcement officers and families had believed until lately that symptom of increased pain (hyperalgesia) was used to get additional opioids by opioid dependent or addicted patients. Morphine has been used as pain medication (analgesic) for over 100 years. Daily use of morphine for extended period causes side effects like constipation, dry mouth, tolerance and addiction. Morphine tolerance was treated with consistent increase in dosage of morphine to achieve optimum pain relief in chronic pain patient suffering with intractable pain. In few cases persistent increased dosage of morphine was followed by increased pain also known as hyperalgesia. Patient suffering with increased pain (hyperalgesia) had frequent visits to physician office for inadequate pain relief. Hyperalgesia was initially diagnosed as inadequate pain relief secondary to tolerance and resistance to opioids and morphine dosage was further escalated to seize the pain intensity. Goal was to keep the pain intensity at tolerable level, improve patient’s activities and quality of life. Instead, hyperalgesia became worse with further increase in morphine daily dosage. Continuous intolerable pain had forced patient to self-medicate with available morphine or other prescribed opioids. Hyperalgesia was overlooked or misdiagnosed. Hyperalgesia in the past was often diagnosed as increased tolerance to opioid or behavior of opioid addiction. Patient more likely was visiting physician’s office for early refill and now patient was labeled as opioid addict.

Morphine Induced Hyperalgesia-Is It Real?

Is Hyperalgesia A Side Effect Of Morphine?

Recent several scientific research papers and studies have documented the diagnosis of hyperalgesia as a side effect of high morphine dosage and similar side effects were also observed with other opioids.

Opioid addict, drug seekers and doctor shoppers will use symptoms of hyperalgesia to get pain medication either for self-ingestion or divert for profit. At present, physicians trained in pain management are better skilled to diagnose these offenders than in the past. Opioid history suggests opioid abuse was known for over 3000 years.

History Of Morphine As A Pain Medication:

Extract of opium seed were used as analgesics for pain relief since 3400 B.C. during Egyptian civilization. Egyptian exploited later during 1300 B.C. opium as euphoric remedies. Egyptians were cultivating opium to trade across sea to Greece and Europe during 1200 B.C. In 460 B.C. Hippocrates “Father of a Medicine” described opium as a useful narcotic for pain medication. Opium was traded for profit across India, China and Europe during 18th century. Opium was smuggled in United State since mid 18th century. Morphine was the first alkaloid extracted from opium in 1804 by Fedrich Sertuner.2 Morphine was marketed as analgesic or pain medicine in 1817 by Sertuner & Co. Diacetylmorphine or heroine was synthesized from morphine in 1874. Bayer distributed heroin in 1898 as analgesics. Heroine and morphine were identified in United State as a narcotic drugs causing addiction during early 19th century. United Sate banned opioids as an illegal drug in 1905. Morphine was considered as controlled substance in United State after Harrison Narcotics Tax Act of 1914. Morphine was extensively used during American Civil War between 1961 and 1965. Following war 400,000 soldiers were diagnosed of morphine addiction. Post civil war morphine addiction was recognized as “Soldier’s disease”.3

Morphine was most valuable pain medication and widely used in U.S. hospitals as analgesics during 19th and 20th century until 1990. Morphine was the main drug used to provide anesthesia and analgesia by Anesthesiologist during surgery. Millions of surgeries were performed every year and morphine became main analgesics of choice until 1990. During recent years life threatening diseases are managed by various advanced surgical procedures. Short acting opioid analgesics such as fentanyl or sufentanyl are more frequently used since 1990 than morphine during anesthesia. Morphine even today continues to be the drug of choice for post-operative pain during hospital stay as well as following discharge to home.

Pain management of chronic cancer and non-cancer patient became major concern after 1985. Physicians were expected to give adequate opioids to achieve optimum pain relief for chronic pain patients. Therapeutic goal was to improve quality of life and activities. Dispensing adequate pain medications become subjective practice, since pain cannot be measured. Pain clinic became alternate source of getting opioids for drug seekers. Demand to get higher dosage of opioids by genuine pain patients and drug seekers increased since 1990 to 2012. Symptoms of opioid tolerance, resistance and dependence were used to obtain higher dosage of opioids. Physicians, nurse practitioners and physician assistant were also under pressure from licensing board and fear of litigation to prescribe enough pain medications to achieve optimum pain relief. Patients and drug seekers did not disclose serious side effects and complications of opioids to treating physicians because of fear that opioid treatment may be discontinued.

How Is Use Of Morphine Linked To Causing Hyperalgesia?

Chronic pain patients receiving morphine for over 6 to 12 months often show signs of morphine induced hyperalgesia. The recent scientific study of molecular origin of increased pain induced by morphine was published in the journal of Nature Neuroscience by Francesco Ferrini, Tuan Trang, Dr. Y. De Konincket all affiliated with University of Laval, Quebec City in Canada. Four research findings identifies molecular pathway causing morphine induced increase pain or hyperalgesia. Research has also identified a target pathway to suppress morphine induced pain. Research does provide the evidence of cause of hyperalgesia induced by morphine. Study also suggests a target pathway to suppress morphine-induced pain. Recently clinical expression of tolerance and hypersensitivity had been discussed in details but now this research has identified cellular and signaling processes of morphine tolerance and hyperalgesia. A pain modulating specialized cell called microglia within spinal cord becomes hypersensitive with increase dosage of morphine. Hypersensitive microglia cells inhibit activities of KCC2 protein. KCC2 protein regulated sensory signal to brain through chloride ion exchange. Inhibition of KCC2 protein triggers increased transmission of impulses to brain and results in hyperalgesia. Restoring the normal KCC2 activity can alleviate the hypersensitivity.

Conclusion: Morphine Use Can Cause Hyperalgesia!

It seems morphine induced hyperalgesia is real and symptoms of hyperalgesia should be identified as and when increased dosage of opioids are needed for pain control. Hyperalgesia should be treated before fatal side effects happen.


  1. Morphine induces hyperalgesia without involvement of ?-opioid receptor or morphine-3-glucuronide.
    Swartjes M, Mooren RA, Waxman AR, Arout C, van de Wetering K, den Hartigh J, Beijnen JH, Kest B, Dahan A.
    Mol Med. 2012 Dec 6;18:1320-6. doi: 10.2119/molmed.2012.00244.
    Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
  2. A brief history of opiates, opioid peptides, and opioid receptors.
    M J Brownstein
  3. http://www.druglibrary.org/schaffer/history/soldis.htm
  4. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl? homeostasis. Francesco Ferrini, Tuan Trang, & Yves De Koninck
    Nature Neuroscience 16, 183–192 (2013) doi:10.1038/nn.3295
    Received 08 October 2012 Accepted 05 December 2012 Published online 06 January 2013.

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Team PainAssist
Team PainAssist
Written, Edited or Reviewed By: Team PainAssist, Pain Assist Inc. This article does not provide medical advice. See disclaimer
Last Modified On:January 21, 2020

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