More opioids, more pain: Fueling the fire

David Boyce, MD


For more than a century, clinicians have noticed a paradoxical phenomenon: certain patients who are taking opioids (which are supposed to numb pain) become more sensitive to pain than those who are not taking opioids.

The earliest observation of this phenomenon can be traced back to the British physician Sir Clifford Allbutt, who, in 1870, described it: “at such times I have certainly felt it a great responsibility to say that 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?” Research studies and clinical observations over the years have identified the phenomenon Dr. Allbutt noticed as opioid-induced hyperalgesia (OIH).

What is opioid-induced hyperalgesia?

Hyperalgesia is an increased pain response from a stimulus (cause) that usually provokes a minor pain response. For example, getting your blood drawn for lab testing usually causes mild discomfort, but this common medical procedure would be very painful for certain patients who are taking opioids chronically. OIH is a lesser known side effect of long-term opioid therapy, but a serious one, and yet another reason doctors should carefully select who may benefit from extended use of these pain medications.

What causes OIH?

The mechanism behind opioid-induced hyperalgesia is complex and involves molecular and chemical changes in the brain and spinal cord. Opioids tend to activate specific receptors that block painful signals from reaching the brain. When these medications are taken for long periods of time, our bodies (as a defense mechanism) try to overcome these blocked signals by activating other pain signals and pathways, a phenomenon known as hypersensitization. These changes reflect the incredible abilities of our brains to form new connections and pathways and alter how the circuits are connected in response to changes, also known as neuroplasticity. A positive example of this would be the rehabilitation process after a stroke: when someone suffers a stroke as a result of a clot or bleed in the brain and becomes unable to use their arm properly, the brain will start forming new connections in an attempt to overcome this deficit, and with proper rehabilitation and training a person may be able to use the arm normally again.

Who is at risk of developing OIH?

Pain perception is a very complex process. Many factors affect how the brain interprets pain signals. Anxiety, depression, genetics, medications, our physical health, and other illnesses can increase or decrease our feeling of pain. Just as pain perception is individual, the level of hyperalgesia is not the same in all patients; some people will experience more hyperalgesia based on their genetics and personal predisposition. Additionally, there is no well-established period of exposure after which OIH occurs, and the exact timing of someone developing OIH varies from patient-to-patient.

What we do know is that people who take opioids regularly are at greater risk of developing OIH. Researchers have looked at many patients who were taking opioids for long periods of time and compared their pain tolerance or pain sensitivity to that of patients who were not taking opioids. Researchers also compared patients’ pain sensitivity before and after starting opioid therapy. In both cases they found that administration of opioids paradoxically increased sensitivity to pain and made pre-existing pain worse, and higher doses of opioids were associated with higher sensitivity to pain.

Recognizing and treating OIH

If you or your doctor aren’t aware of this phenomenon, and you are prescribed more opioids to treat increased pain sensitivity, it can lead to a vicious cycle of increasing the dose of opioids and more pain, as well as an increased risk of overdose. The appropriate approach to treating OIH is to wean slowly from a high dose of opioids, which usually requires time and patience. During this time, it may be appropriate to add non-opioid alternatives to managing pain, such as other medications, injections, behavioral interventions, and physical therapy. You doctor may also recommend avoiding opioids altogether, or taking an “opioid holiday” so your body can recover. Working closely with your healthcare team is very important, as is managing your pain during a weaning period. There are CDC guidelines available to help your doctor safely taper your dose.

Historically, opioids were used to treat pain caused by end-stage advanced cancer, or for acute pain (after surgery, a bone fracture, a serious accident, etc.), and only for a short period of time (a few days), to reduce the risk of side effects. Unfortunately, there has been a drastic increase in the use of opioids in the United States over the last two decades for the treatment of chronic non-cancer pain (back pain, arthritis, etc.), and some people have taken opioids for longer than medically necessary for their type of pain.

While opioids definitely have their place in medical practice, we need to be aware of the serious side effects of these medications, including side effects that may cause more suffering, like OIH, as well as lethal side effects such as overdose. If you think you or a loved one may be experiencing OIH, you should discuss this with you doctor, and work with them to taper your dose and find alternatives to manage your pain safely.


A Comprehensive Review of Opioid-Induced Hyperalgesia. Pain Physician, March/April 2011.

Opioid-induced Hyperalgesia: A Qualitative Systematic Review. Anesthesiology, March 2006.

Opioid Induced Hyperalgesia. Pain Medicine, October 2015.


  1. Shafik Boyaji

    Stuart, while I applaud your efforts to pull these data, I think you are missing the big picture. The correct name of this epidemic is “Opioid-Addiction crisis”. And the word opioid here is a broader term that includes opioids/opiates and any substance, natural or synthetic, that binds to the brain’s opioid receptors (Hydrocodone, Oxycontin, Heroin, Methadone, etc). What you are pointing at, the increased number of overdose death by heroin and fentanyl, is only the dark end of the opioid-use disorder. You need to understand that these patients didn’t wake up one day and started injecting Heroin and Fentany, their unfortunate journey started many years ago, and as most facts reviling, it started with opioid prescriptions because there were abundance of these pills in the community over the last two decades. Just to put things into prospective and give a small example, it was estimated that, at one point, 21 million hydrocodone and oxycodone pills had been delivered to Williamson, WV, a town with fewer than 3,200 residents!
    While you presented some facts “Opioid prescribing is presently at its lowest volume in the previous 15-years” it is still misleading. After 1995 with the aggressive marketing and liberalization of opioid prescription habits, the prescription numbers has increased many folds, that with all the efforts that has been done so far, the prescription numbers still more than three times the numbers in 1999 and overall it is nearly Four times as high the amount distributed in Europe*.
    While you also presented straight-up misinformation “the lack of correlation between the number of opioid prescriptions and the number of overdoses”, it has been shown clearly that opioid–related overdose deaths increased substantially in parallel with increased prescribing of opioids**.
    So if you looked at the big picture and studied the root of this crisis, it was the “opioid prescriptions” that fueled the crisis and created this large pool of individuals with opioid-use disorder that went later on to use illicit opioids.
    Finally, and I think most importantly, you used many “inflammatory” phrases in your discussion, words like (and I am quoting you) “opioid hysteria” and “government’s misdirected prescription drug prohibition program”. No one is running a “prohibition” program, but there is a huge epidemic that declared more than 400,000 lives over the last two decades*** and all the efforts of the medical community are aiming toward correcting and treating this problem, while keeping in mind the safety and the well-being of chronic pain patients. Phrases like this will not help anyone, especially chronic pain patients.
    * Guy GP Jr., Zhang K, Bohm MK, et al. Vital Signs: Changes in Opioid Prescribing in the United States, 2006–2015. MMWR Morb Mortal Wkly Rep 2017;66:697–704.
    ** Schuchat A, Houry D, Guy GP. New Data on Opioid Use and Prescribing in the United States. JAMA. 2017;318(5):425–426.
    *** Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved Overdose Deaths – United States, 2013-2017. WR Morb Mortal Wkly Rep. ePub: 21 December 2018.

  2. Lawrence Feldman

    Something established in lab rodents, but infrequently found in human patients. Almost to the point of ‘Urban Myth’.

    • Shafik Boyaji

      Lawerence, I don’t think you read the article well. This phenomenon FREQUENTLY found in humans, plenty of evidence out there in studies and clinical practice, please refer to the articles by the end. Mentality like this has lead to the opioid epidemic by ignoring and not respecting the evidence and the convention medical wisdom that accumulated over the years.

      • David J. Littleboy

        Thanks for replying! (I’d like to see more replies by authors here.)

        I grew up in the 60s, and between the hippies, jazz and rock musicians, and the many Vietnam vets exposed to heroin in Vietnam, we learned the hard way that opioids are a really bad idea. I’ve lived outside the US the last 30 years, and was horrified when I fist started reading about the opioid epidemic. How could we have possibly forgotten that hard-learned lesson so quickly. Sigh. (Here in Japan, a nasty bout of acute back pain got me a prescription for half-strength OTC pain killers and physical therapy; in the US I’d have been a statistic.)

        It’s a horrific irony that science has shown that opioids are worse than OTC pain medication for chronic pain. And that the strongest pushback from attempts at reversing the insane over-prescription of opioids in the US is coming from chronic pain patients.

        Whatever. Please, keep up the science-based reporting. Thanks again.

      • Stuart

        Here are some revealing statistics accumulated from government websites, data bases, etc.

        According to the current heavy-handed government policies intended to reduce opioid overdoses, the “opioid crisis” was initiated by the noticeable increase in opioid prescriptions that started in the late 1990s. A generally accepted assumption that has never really been scrutinized.

        However, it has become apparent that many of the government’s current policies that were likely inspired by the “over prescription” assumption have turned out to be wholly ineffective, and very likely doing more harm than good.

        Opioid-related deaths have risen by approximately 500% since 1999 despite the fact that per capita “high-dose” prescriptions, defined as 90 morphine milligram equivalents (MME) or greater fell by 58% from 2008 to 2017, all while the total number of opioids dispensed also fell by 29% from 2010 to 2017.

        Since 2010, deaths involving heroin and fentanyl have risen much more dramatically than those involving prescription opioids. The share of opioid-related deaths involving “synthetic opioids other than methadone” rose from 14% in 2010 to 60% in 2017. According to the Drug Enforcement Administration (DEA), “that category consists almost entirely of illicitly produced fentanyl and fentanyl analogs, manufactured in Asia or Mexico and smuggled into the United States.”

        Per the CDC, fentanyl and/or heroin were involved in approximately 75% of opioid-related deaths in 2017, up from 28% in 2010. Just 30% of opioid-related deaths involved prescription analgesics such as hydrocodone and oxycodone in 2017, down from 52% in 2010, and roughly 40% of those 2017 cases that also involved heroin or fentanyl. Roughly 18% of total “opioid-related” deaths in 2017 involved some type of prescription medication without heroin and/or fentanyl.

        Opioid prescribing is presently at its lowest volume in the previous 15-years while overdose deaths involving opioids continue to escalate annually. Opioid prescriptions are 300% higher for seniors (people over age 51) compared to young people (people under age 51). Older people are obviously much more likely to be treated for chronic painful conditions. Yet, the rate of opioid overdose deaths in people above age 51 is the lowest for all age groups while they are prescribed opioids at a 300% higher rate than people under the age of 55.

        Overdose deaths among young adults (people under age 51) are six times higher than people above age 51, e.g., the age group that has the least number of (legal) opioid prescriptions is overdosing at a rate six times higher than the age group that has 300% more opioids prescribed to them.

        This information suggests that the current opioid crisis (opioid hysteria) is very likely one of the unintended consequences of government’s misdirected prescription drug prohibition program.

        The demographics of the overdose deaths attributed to opioids are conspicuously different from those of actual pain patients, e.g., the number of overdose deaths compared to the total number of opioid prescriptions for the majority of geographical areas do not correlate. Statistically, there is no “cause-and-effect” between the number of opioid prescriptions and the number of overdoses. This lack of correlation would more likely indicate that it was illicit narcotics, not over prescribing that fueled the opioid crisis.

        And that prescriptions are not the primary driving component of the deceptively named “opioid crisis.” We have been experiencing is an “illicit heroin and fentanyl crisis.” And current heavy-handed government policies aimed at reducing opioid overdoses seem to be misdirected and likely further contributing to the problem.

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