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The 21st century opioid epidemic began through a series of events that resulted in significant relaxation of criteria for opioid prescribing and a willingness to prescribe much higher doses than had been seen previously. It was due to drug company pseudoscience, legislatures and medical boards who rolled back restrictions on prescribing and developed new legislation to promote medical prescribing, quasi-governmental agencies such as JCAHO adoption of the "5th Vital Sign", pain society promotion of opioids, inadequate basis for "board certification" of physicians prescribing pain medications, naivite of doctors that in some cases turned to insouciance as they prescribed ever escalating dosages for increasingly flimsy reasons, doctors turned drug dealer as a criminal enterprise, and patients who clamored for greater access to opioids through patient advocacy groups. The culmination of years of escalating dosages and deaths produced a bubble of millions of patients that are chemically dependent, some of which much later turned to heroin. Below is a timeline I created to demonstrate the origins of the current epidemic.
• 1950 Percodan FDA approved
• 1952 Purdue Frederick, a small struggling pharmaceutical company founded by doctors John Purdue Gray and George Frederick Bingham in 1892 operating in New York City, was purchased by three psychiatrist brothers Raymond Sackler (1920-2017), Arthur Sackler (1913-1987), and Mortimer Sackler (1916-2010) of New York City. Purdue Pharma L.P. was formed in 1991 as one of the branches of the company and is the namesake it is known by in sales and business. Purdue Frederick Laboratories (Totowa New Jersey). Purdue began developing pain management medications. By 2015 the Sackler family became the 16th most wealthy family in the country with assets of $14 billion dollars, nearly all due to Oxycontin. Purdue has had sales totaling $35 billion since 1995 when Oxycontin was approved. (Forbes, July 1, 2015)
• 1954 Levorphanol tartrate (Levo-Dromoran) introduced
• 1960 Fentanyl synthesized by Paul Janssen. It was approved for IV use as a combination drug with droperidol in 1968, a combination that was believed to limit abuse potential of the IV drug due to the significantly bad psychiatric effects of the droperidol at high dosage. The combination drug, Innovar, was produced after pure fentanyl ran into roadblocks in the FDA approval process and was staunchly opposed by the venerable field leader Robert Dripps, MD. Once a compromise was reached between Dripps and Janssen with fentanyl being formulated in combination with droperidol, it was used in neuroleptanalgesia. In 1972, IV fentanyl was approved by the FDA as a single drug in 1ml vials, 50mcg/ml. (J Pain 2014;15(12):1215-26)
• 1970 British Medicine Journal article stating “Intractable pain of non-malignant origin is nearly always best treated other than by narcotic analgesics since their continued use must lead to dependence.” “Tolerance develops relatively quickly- sometimes a dosage of 500mg of morphine a day is reached within 10 days”. (Br Med J. 1970 May 30;2(5708):525-6
• 1973 International Association for the Study of Pain (IASP) formed
• 1974 Percocet FDA approved (Schedule II drug)
• 1977 American Pain Society (APS) formed as a component society of the IASP
• 1977 The prevailing attitude was that opioids for chronic non-malignant pain should be avoided. (Analgesic drugs in the management of pain. Halpern L. Arch Surg 1977 Jul;112(7):861-9) “The use of potent narcotics to control severe pain should be of short duration and limited to patients with acute diseases or inoperable or metastatic cancer who require long-term relief. Continued and prolonged use of narcotics in patients with chronic benign pain is not recommended because of serious behavioral consequences, the development of tolerance, and addiction liability. Long-term use of analgesic drugs in chronic pain usually produces negative behavioral complications that are more difficult to manage than the pain it was desired to eliminate.”
• 1978 Vicodin 5/500 approved by FDA (Knoll Pharmaceutical) as a Schedule III drug, permitting up to 5 refills, could be called in to a pharmacy without a written prescription, and with recommended maximum dosing 8 tabs per day due to the acetaminophen (40mg hydrocodone).
• 1978 Colpaert FC published an article “Long-term suppression of pain by narcotic drugs in the absence of tolerance development” (Arch Int Pharmacodyn Ther. 1978Dec;236(2):293-5)
• 1979 A rat study demonstrated chronic pain alone produces hypoalgesia, chronic narcotics alone cause hyperalgesia, tolerance to narcotics in animals with chronic pain may not develop. (Colpaert F, Life Sciences 1979 Mar26;24(13):1201-9)
• 1980 Jane Porter and Hershel Lick wrote a letter to the NEJM entitled “Addiction Rare in Patients Treated with Narcotics”, describing 4 cases of addiction in 11,882 hospitalized patients receiving opioids identified by the Boston Collaborative Drug Surveillance Project. Patients received at least one dose of opioid as part of their medical treatment. They wrote that "the development of addiction is rare in medical patients with no history of addiction." This one paragraph letter was used extensively by opioid manufacturers in the 1990s to demonstrate the very low rate of addiction in opioid users.
• 1980 Forest S. Tennant Jr. MD of the UCLA School of Public Health published medical-legal guidelines for prescribing narcotics to habitual and addicted narcotic users in California and western states. In this paper (West J Med Dec 1980;133(6):539-45) he laid the legal framework within confines of a medical practice of treatment of pain in addicts and described the ability and restrictions on treating addicts. In particular with dual diagnosis he made a legitimate case for prescribing opioids for chronic pain patients.
• 1980 The American Chronic Pain Association was formed as an advocacy and education group for chronic pain patients.
• 1981 Buprenorphine (injectable) “Buprenex” approved by the FDA
• 1982 S Perry and G Heidrich published a study entitled “Management of pain during debridement: a survey of US burn units” (Pain 1982;13:267-280) In this study of 10,000 burn patients, there were no reported cases of addiction. This study was extensively used in advertising by opioid manufacturers to sell their medications.
• 1983 Forest Tennant published an article describing (-)alpha-Acetylmethadol (LAAM) for the treatment of chronic pain in abusers of opioids. In 3 of 4 patients, pain was relieved and opioid abuse was eliminated (Drug Alcohol Depend. Nov 1983;12(3):243-7) He concluded LAAM may be very helpful in the treatment of chronic pain, especially given the 72 hour half life of the drug
• 1983 American Academy of Algology founded taken from the name algos, Greek for pain, and logy- Greek for study. However, “algology” was long in use by the scientific community for the study of algae. In 1985, the American Academy of Algology changed their name to the American Academy of Pain Medicine . This organization was significantly supported by opioid manufacturers later in time according to New York Times, US Government, and this author’s personal attendance at their annual meetings.
• 1984 First annual meeting of the American Academy of Algology
• 1984 Dilaudid and Dilaudid HP FDA approved (Schedule II drug).
• 1984 A study on slow release oral morphine showed no correlation between analgesia and plasma level of morphine. (Vater M, Smith G, Aherme GW Pharmacokinectics and analgesic effect of slow-release oral morphine sulphate in volunteers Br J Anaesth 1984 Aug;56(8):821-7) <This reinforced the concept of titration to analgesia instead of fixed amount dosing for pain, and justified escalating doses.>
• 1984 A letter to the editor entitled “Pain, the physiological antagonist of opioid analgesics” (GW Hanks, RG Twycross Lancet June 30 1984;1(8392):1477-8) contended that pain itself reduced the effects of analgesics, implying a measure of safety if pain were present during their use.
• 1986 Russell Portenoy and Kathleen Foley published a paper on the use of mainly low dose opioids among 38 non-cancer patients with no reported misuse/addiction. This small study was widely quoted by drug manufacturers and champions of opioid prescribing for the next 25 years as evidence of low addiction risk. Specifically, the authors concluded in the prestigious journal Pain, [25(1986):171-86] “For non-cancer pain, narcotics “can be safely and effectively prescribed to selected patients with relatively little risk of producing the maladaptive behaviors which define opioid abuse.” (Gounder, C. New Yorker Magazine, Nov. 8, 2013)
• 1986 World Health Organization develops their analgesic ladder, including opioids, and encouraged the treatment of cancer pain with opioids
• 1986 Nyswander ME and Dole VP Published a paper “On the use of methadone to limit physical dependence in the treatment of chronic pain” (In: Foley KM, Inturrisi CE, editors. Advances in Pain Research and Therapy. Vol. 8. New York: Raven Press; 1986. pp. 187–190). This article may have promoted the prescribing of methadone for chronic pain. Methadone later turned out to have ten times the rate of death compared to other opioids.
• 1987 MS Contin approved by FDA and was marketed exclusively for cancer pain initially according to the 2003 GAO report on Oxycontin
• 1987 Cephalon founded by Frank Baldino (pharmacologist), Michael Lewis (neuroscience), and James C. Kauer (organic chemist), all three former scientists with DuPont. Cephalon developed Actiq, Fentora, Nuvigil, and Provigil. In 2008 Cephalon paid 425 million to the federal government due in part to marketing Actiq for off label uses. Cephalon was acquired by Teva in 2011.
• 1987 Utah board of medicine established guidelines regarding the use of controlled substances to treat pain
• 1988 Study on hydromorphone blood levels and pain control concluded “Knowing that there is a low concentration of narcotic in the blood of a patient with chronic severe pain who is receiving high drug doses and who shows lack of both efficacy and side effects may reassure health care professionals that further narcotic dosage escalation is appropriate.” MM Reidenberg et al Clin Pharmacol Ther 1988 Oct;44(4):376-82)
• 1988 Forest Tennant, D. Robinson, A Sagherian, and R Seecof published a paper (NIDA Res Monogr 1988;81:174-80) that discusses a systematic clinical evaluation of 52 chronic non-malignant pain patients with a mean age of 49 years, evenly divided male/female, that were referred for treatment of severe intractable pain after having failed several other therapies. “Once pain relief was achieved, patients did not escalate their dosage, and they were able to maintain pain relief for long time periods. Opioids used were different for different patients and had a daily dosage range of hydromorphone 8-120mg, methadone 10-240mg, oxycodone 15-80mg, meperidine 200-2000mg, and morphine 60mg. Although opioids produced dependence in all patients and complications of constipation and edema in about one third, high daily opioid dosage treatment appeared to be the only medical means to achieve adequate pain control in these subjects”. The author measured plasma levels of these drugs and found several of those taking codeine and some taking methadone had no detectable levels of these drugs.
• 1988 Minnesota board of medicine established guidelines regarding the use of controlled substances to treat pain and Virginia established intractable pain policies
• 1988 American Academy of Pain Management founded and later began offering “Certificates in Pain Management” to non-physicians after paying a fee then taking a short written test. This organization changed their name to the Academy of Integrative Pain Management in 2016
• 1988 American Medical Association recognizes Pain Medicine as a specialty and that year the American Academy of Pain Medicine seated its first member in the AMA House of Delegates
• 1989 Massachusetts board of medicine issued guidelines regarding use of controlled substances to treat pain, Texas launched an intractable pain treatment policy
• 1989 Weissman & Haddox created the term “pseudoaddiction” based on their experience with a 17 year old leukemia patient with chest wall pain who appeared to be addicted due to inadequate pain medication. (Pain 1989 Mar;36(3):363-6) This term was later used by opioid manufacturers to promote opioid overuse and by addicts to justify higher doses should be prescribed by physicians. Haddox later became Vice President of Health Policy at Purdue, manufacturer of Oxycontin
• 1989 Review article “Opioids in chronic pain” by HJ Mcquay noted “patients who are prescribed opioids for the management of sensitive pain do not become addicts. To deprive them of this means of pain relief is unjust.” HJ McQuay Br J Anesthes.1989 Aug 63 (2):213-219
• 1989- The term “breakthrough pain” first appeared in the medical literature (Cancer 1989;63:2284-2288), coined by Russell K. Portenoy, M.D., Mathelyn Maldonaldo, RN, Ronald Fitzmartin PhD, Robert F. Kaiko PhD, and Ronald Kanner, MD in an article regarding cancer patients receiving MS Contin for pain. Portenoy was the principle author and published at least 26 other articles regarding “breakthrough pain”.
• 1990- The venerable R. Melzack published “The tragedy of needless pain” in the widely read Scientific American magazine [Sci Am. 1990 Feb; 262(2):27-33.] and this article was considered seminal in enhancing prescribing of opioids for chronic non-malignant pain. In this article he stated: “ Many people suffer not because their discomfort is untreatable but because physicians are often reluctant to prescribe morphine…many care givers, afraid of turning patients into addicts, deliver amounts that are too small or spaced too widely to control pain. Yet the fact is that when patients take morphine to combat pain, it is rare to see addiction.”
• 1990 RK Portenoy and NA Hagen characterized “breakthrough pain”, and published an article about its characteristics. (Pain 1990; 41:273-81)
• 1990 Russell Portenoy and Kathleen Foley along with C. Inturrisi published a paper in Pain 1990 Dec;43(3):273-86 stating “opioids should not be withheld on the assumption that pain mechanism, or any other factor, precludes a favorable response. “….the clinical use of opioids should include dose escalation to maximally tolerated levels and repeated monitoring of analgesia and other effects” “In 1990 Russell Portenoy was quoted in other journal articles advocating for the use of opioids for chronic non-malignant pain (J Pain Symptom Manage. 1990 Feb;5(1 Suppl):S46-62.
• 1990 Fibromyalgia was coined and used to justify the treatment of pain without any objective signs or symptoms, without any known cause or pathophysiology
• 1990 Clinical Journal of Pain established as the American Academy of Pain Medicine’s first official journal
• 1990 Arizona state medical board issued guidelines regarding the use of controlled substances to treat pain and California developed an Intractable Pain Therapy Act, Section 2241.5. California’s policy specifically stated “No physician or surgeon shall be subject to disciplinary action by the board for prescribing or administering controlled substances in the course of treatment of a person for intractable pain” with the exception the patient may not being treated for chemical dependency or with medications used for a non-medical purpose.
• 1990 Duragesic approved by FDA (Schedule II drug) and was used primarily for cancer pain initially. The initial studies in fentanyl patch technology was from Alza, a small pharmaceutical company that began working on the technology in 1984 after developing a commercially successful scopolamine patch.
• 1991 S Schug, A Merry, and R Acland published an article in Drugs [1991Aug;42(2):228-39] stating “Inadequately treated acute and chronic pain remains a major cause of suffering, in spite of enormous advances in pharmacology and technology. Opioids provide a powerful, versatile, widely available means of managing this pain, but their use is too often restrained by ignorance and mistaken fears of addiction. However, problems (such as tolerance, physical dependence, addiction and chronic toxicity), anticipated from experience with animal experiments and pain-free abusers, seldom cause difficulties when opioids are used appropriately to treat pain (so-called 'dual pharmacology'). “
• 1991 Postgraduate Medicine article Morphine myths: sedation, tolerance, addiction was published (67 Suppl 2 S100-2) by M. Zenz who argued “Morphine and other strong opioids are still, more than 180 years after the synthesis of morphine, not adequately used in clinical practice and many patients suffer unnecessarily severe pain in consequence. Governments limit morphine usage by legal restrictions. The underuse of morphine and its restriction in many countries is mostly due to prejudice and myths which clinical experience does not show to be true. Morphine is a very safe drug, correctly prescribed in chronic pain therapy, the only severe side effect being constipation.”
• 1991 Brian Goldman, MD published a paper (CMAJ. 1991 Jun 15;144(12):1660-4.) entitled “Analgesics and chronic pain: “If all you have is a hammer, every disease is a nail” exploring opioid use in chronic non-malignant pain. In this paper, Russell Portenoy is quoted saying about “several large prospective studies that were completed in the 1980s with surprising results: “They concluded that the documented incidence of iatrogenic addiction to prescribed narcotic painkillers was of the order of 4 cases per 10,000 patients. These data suggest that patients with no prior history of alcoholism or abuse or street drugs are at extremely small risk of developing these behaviors when given opiate drugs therapeutically for the treatment of pain.”
• 1991 Oregon and Georgia medical boards issued guidelines regarding the use of controlled substances to treat pain
• 1991 Oramorph FDA approved as a Schedule II drug (Roxane Laboratories)
• 1991 American College of Pain Medicine founded (became the American Board of Pain Medicine in 1994)
• 1992 Russell Portenoy published an article “Chronic Opioid Therapy for Non-Malignant Pain: From Models to Practice” (APS Journal later known as Pain Journal 1992;1(4):285-88) In this journal he fully makes the transition from treatment of cancer pain to non-cancer pain with opioids. “The general applicability of a biopsychosocial model of chronic pain might lead to the expectation that some patients with nonmalignant pain respond to opioid therapy in a manner that mirrors the typically favorable response of the cancer pain patient, just as some patients with cancer pain demonstrate psychological disturbances and disabilities reminiscent of a severe chronic nonmalignant pain syndrome. The most reasonable approach is probably one that is commonly accepted for other inadequately studied analgesic treatments, namely, empirical patient selection followed by a therapeutic trial. The concept of the therapeutic trial has not been applied to the use of opioids for chronic nonmalignant pain, despite the lack of any compelling reason to avoid the approach.” Portenoy goes on to critique the guidelines for opioid prescribing for chronic non-malignant pain created by Dr. Chabal and colleagues, who advocated of only one formulation of a single opioid drug, inform their patients ‘the more you take it, the less it works’, and that additional medication requests are automatically refused suggesting the patient has a drug problem. Portenoy argues for “flexibility” in opioid use, that there is “evidence in the clinical literature analgesic efficacy seldom declines over time unless there is worsening in the underlying pathology”, and that requests for higher doses may have multiple causes including pseudoaddiction, tolerance, worsening underlying pain in addition to addiction. He also notes Dr Chabal neither mentioned a therapeutic trial nor a “treatment holiday”, and there was no discussion of the “need for sophistication in opioid pharmacotherapy”.
• 1992 Russell Portenoy and R Payne published a chapter “Acute and chronic pain in “Comprehensive Textbook of Substane Abuse” Baltimore: Williams Wilkins 1992;714 in which 25,000 pain patients treated with opioid narcotics were reviewed and found only 7 demonstrated a “true addictive lifestyle” with the risk of true addiction 0.3% of the population suffering with chronic non-malignant pain.
• 1992 E. Richard Blonsky, MD became president of the American Academy of Pain Medicine
• 1992 Zenz, Strumpf, and Tryba published a paper describing long term treatment of 100 patients with opioids for chronic pain (J Pain Symptom Manage 1992 Feb;7(2):69-77) with morphine (daily dose mean 255mg with a range of 20-2000mg/day) stating 51% received good pain relief, 28% partial pain relief, and 21% did not have good pain relief in a mean 7 month treatment period. Functional improvement was directly correlated to reduction in pain. They also concluded there was no cases of addiction and no side effects other than nausea and constipation, and “Our results indicate that opioids can be effective in chronic nonmalignant pain”
• 1992 Colorado developed an intractable pain treatment policy
• 1992 the Agency for Health Care Policy and Research developed a policy on the assessment of post-operative pain stating “opioid analgesics are the cornerstone of pharmacological postoperative pain management” and “psychological dependence and addiction are extremely unlikely to develop after patients without prior drug abuse histories use opioids for acute pain”. They also stated initial postoperative dosing should be on a scheduled basis rather than prn, then later may use Q4H prn dosing. <the encouragement of post op pain opioid dosing by physicians ultimately led to chronic use and an increase in the rate of addiction>
• 1992 First board certification of physicians practicing pain by the American College of Pain Medicine
• 1992 First board certification of pain physicians by the American Board of Anesthesiology- hundreds of doctors from 1992-1998 without any formal pain training at all were certified by the board as having “Specialized qualifications in pain management” after taking a written test. Hundreds of physicians could now claim “board certification in pain medicine” without training, opening up a pandora’s box of opioid prescribing.
• 1992 American Academy of Pain Medicine incorporated in Illinois
• 1993 Oralet (fentanyl solid sweetened “lollipop” lozenge was released by Abbott Laboratories as a Schedule II drug for preoperative drug sedation in children in the hospital setting and for treatment of painful procedures in adults and children. It was developed beginning in 1985 by Theodore H Stanley with clinical trials beginning in the late 1980s. Janssen declined to bring it to FDA approval so another company was formed, Anesta to develop oral transbuccal fentanyl citrate. During pre-approval clinical trials with Oralet, Drs. Perry Fine and Michael Ashburn contemplated the use of the drug in cancer patients for break through pain, a term championed by Portenoy. Oralet was later withdrawn due to nausea from the drug. The blood levels achieved were much lower than the later released Actiq and Fentora.
• 1993 Alaska, Texas, and Wyoming state boards of medicine issued guidelines regarding the use of controlled substances to treat pain and Washington issued an intractable pain treatment policy
• 1993 First ACGME accredited pain fellowships beginning with approximately 35 programs. These programs from 1993-2000 were taught by mainly by anesthesiology faculty, doctors that primarily were operating room or labor pain doctors at the time. “As a result, many new pain specialists were intellectually or clinically unprepared by their formal training to assimilate the burden of managing chronic pain” (Bonica’s Management of Pain by Scott Fishman published 2012 p. 1560) The first multidisciplinary requirements for fellowship training in pain medicine were not implemented until 2006 implying many doctors trained in fellowship before that point potentially had inadequate training in chronic pain management. Bonica, the father of pain medicine recognized the need for a multidisciplinary approach in 1947
• 1993 Purdue launched Partners Against Pain according to a website, a program designed to connect patients with pain management therapies including opioids. The Partners Against Pain website contained many articles with misinformation, attempting to downplay the addictiveness of opioids and overstating their safety (https://www.fda.gov/ohrms/dockets/dockets/01n0256/c000297-A.pdf)
• 1994 Robert N Jamison PhD, Karen O. Anderson PhD, Christine Peeters-Asdourian MD, and Michael F. Ferrante MD published a paper “Survey of opioid use in chronic nonmalignant pain patients” Regional Anesthesia Jul-Aug 1994;19(4):225-30 Two hundred seventeen patients being treated for pain at two pain centers completed a questionnaire, and one hundred twelve were taking oral opioids for pain. Of those taking opioids, 83% felt that opioids were moderately beneficial in relieving their pain, 25% believed the opioid had not lost its ability to relieve the pain over time, and 35% reported no need to increase their medication. 36% expressed no fear of addiction or dependence, and 56% had no unwanted side effects.
• 1993 American Academy of Pain Medicine inaugurates its Comprehensive Review Course in Pain Medicine
• 1994 the International Association for the Study of Pain defined chronic pain as a clinical entity distinct from acute pain or “pain”.
• 1994 the Agency for Health Care Policy and Research developed a policy on the assessment of cancer pain.
• 1994 California Board of Medicine adopts guidelines for opioid prescribing: Except for gross negligence, “A physician and surgeon may prescribe for, or dispense or administer to, a person under his or her treatment for a medical condition dangerous drugs or prescription controlled substances for the treatment of pain or a condition causing pain, including, but not limited to, intractable pain. (b) No physician and surgeon shall be subject to disciplinary action for prescribing, dispensing, or administering dangerous drugs or prescription controlled substances in accordance with this section." Alabama state medical board issued guidelines regarding the use of controlled substances to treat pain and Florida issued a pain treatment policy for intractable pain.
• 1995 the American Pain Society conducted a quality improvement oriented literature review on the treatment of acute and cancer pain concluding: (a) a report of unrelieved pain raises a “red flag” that attracts clinicians’ attention (b) making information about analgesics convenient where orders are written (c) promising patients responsive analgesic care and urging them to communicate pain (d) implementing policies and safeguards for the use of modern analgesic technologies; and (e) coordinating and assessing implementation of these measures (JAMA 1995 Dec 20;274(23):1874-80)
• 1995 December 12, the FDA approved Oxycontin (Purdue Frederick Pharma) in dosages of 10, 20, and 40mg “for the treatment of moderate to severe pain lasting more than a few days”. The 80 and 160mg tablets were approved later. The highest dosage tablet was equivalent to 24 tablets of 10mg hydrocodone or 48 tablets of 5mg hydrocodone.
• 1995 Idaho state medical board issued guidelines regarding the use of controlled substances to treat pain, and Missouri, Oregon, and Nevada issued an intractable pain treatment policy. (
• 1995 The American Pain Society introduced the concept of pain as a vital sign in a November 1995 presidential address of James Campbell, MD, not as a directive. Dr. Campbell stated “Vital signs are taken seriously. If pain were assessed with the same zeal as other vital signs are, it would have a much better chance of being treated properly. Quality care means that pain is measured and treated.” (Campbell JN. APS 1995 Presidential address. Pain Forum. 1996;5:85–8)
• 1950 Percodan FDA approved
• 1952 Purdue Frederick, a small struggling pharmaceutical company founded by doctors John Purdue Gray and George Frederick Bingham in 1892 operating in New York City, was purchased by three psychiatrist brothers Raymond Sackler (1920-2017), Arthur Sackler (1913-1987), and Mortimer Sackler (1916-2010) of New York City. Purdue Pharma L.P. was formed in 1991 as one of the branches of the company and is the namesake it is known by in sales and business. Purdue Frederick Laboratories (Totowa New Jersey). Purdue began developing pain management medications. By 2015 the Sackler family became the 16th most wealthy family in the country with assets of $14 billion dollars, nearly all due to Oxycontin. Purdue has had sales totaling $35 billion since 1995 when Oxycontin was approved. (Forbes, July 1, 2015)
• 1954 Levorphanol tartrate (Levo-Dromoran) introduced
• 1960 Fentanyl synthesized by Paul Janssen. It was approved for IV use as a combination drug with droperidol in 1968, a combination that was believed to limit abuse potential of the IV drug due to the significantly bad psychiatric effects of the droperidol at high dosage. The combination drug, Innovar, was produced after pure fentanyl ran into roadblocks in the FDA approval process and was staunchly opposed by the venerable field leader Robert Dripps, MD. Once a compromise was reached between Dripps and Janssen with fentanyl being formulated in combination with droperidol, it was used in neuroleptanalgesia. In 1972, IV fentanyl was approved by the FDA as a single drug in 1ml vials, 50mcg/ml. (J Pain 2014;15(12):1215-26)
• 1970 British Medicine Journal article stating “Intractable pain of non-malignant origin is nearly always best treated other than by narcotic analgesics since their continued use must lead to dependence.” “Tolerance develops relatively quickly- sometimes a dosage of 500mg of morphine a day is reached within 10 days”. (Br Med J. 1970 May 30;2(5708):525-6
• 1973 International Association for the Study of Pain (IASP) formed
• 1974 Percocet FDA approved (Schedule II drug)
• 1977 American Pain Society (APS) formed as a component society of the IASP
• 1977 The prevailing attitude was that opioids for chronic non-malignant pain should be avoided. (Analgesic drugs in the management of pain. Halpern L. Arch Surg 1977 Jul;112(7):861-9) “The use of potent narcotics to control severe pain should be of short duration and limited to patients with acute diseases or inoperable or metastatic cancer who require long-term relief. Continued and prolonged use of narcotics in patients with chronic benign pain is not recommended because of serious behavioral consequences, the development of tolerance, and addiction liability. Long-term use of analgesic drugs in chronic pain usually produces negative behavioral complications that are more difficult to manage than the pain it was desired to eliminate.”
• 1978 Vicodin 5/500 approved by FDA (Knoll Pharmaceutical) as a Schedule III drug, permitting up to 5 refills, could be called in to a pharmacy without a written prescription, and with recommended maximum dosing 8 tabs per day due to the acetaminophen (40mg hydrocodone).
• 1978 Colpaert FC published an article “Long-term suppression of pain by narcotic drugs in the absence of tolerance development” (Arch Int Pharmacodyn Ther. 1978Dec;236(2):293-5)
• 1979 A rat study demonstrated chronic pain alone produces hypoalgesia, chronic narcotics alone cause hyperalgesia, tolerance to narcotics in animals with chronic pain may not develop. (Colpaert F, Life Sciences 1979 Mar26;24(13):1201-9)
• 1980 Jane Porter and Hershel Lick wrote a letter to the NEJM entitled “Addiction Rare in Patients Treated with Narcotics”, describing 4 cases of addiction in 11,882 hospitalized patients receiving opioids identified by the Boston Collaborative Drug Surveillance Project. Patients received at least one dose of opioid as part of their medical treatment. They wrote that "the development of addiction is rare in medical patients with no history of addiction." This one paragraph letter was used extensively by opioid manufacturers in the 1990s to demonstrate the very low rate of addiction in opioid users.
• 1980 Forest S. Tennant Jr. MD of the UCLA School of Public Health published medical-legal guidelines for prescribing narcotics to habitual and addicted narcotic users in California and western states. In this paper (West J Med Dec 1980;133(6):539-45) he laid the legal framework within confines of a medical practice of treatment of pain in addicts and described the ability and restrictions on treating addicts. In particular with dual diagnosis he made a legitimate case for prescribing opioids for chronic pain patients.
• 1980 The American Chronic Pain Association was formed as an advocacy and education group for chronic pain patients.
• 1981 Buprenorphine (injectable) “Buprenex” approved by the FDA
• 1982 S Perry and G Heidrich published a study entitled “Management of pain during debridement: a survey of US burn units” (Pain 1982;13:267-280) In this study of 10,000 burn patients, there were no reported cases of addiction. This study was extensively used in advertising by opioid manufacturers to sell their medications.
• 1983 Forest Tennant published an article describing (-)alpha-Acetylmethadol (LAAM) for the treatment of chronic pain in abusers of opioids. In 3 of 4 patients, pain was relieved and opioid abuse was eliminated (Drug Alcohol Depend. Nov 1983;12(3):243-7) He concluded LAAM may be very helpful in the treatment of chronic pain, especially given the 72 hour half life of the drug
• 1983 American Academy of Algology founded taken from the name algos, Greek for pain, and logy- Greek for study. However, “algology” was long in use by the scientific community for the study of algae. In 1985, the American Academy of Algology changed their name to the American Academy of Pain Medicine . This organization was significantly supported by opioid manufacturers later in time according to New York Times, US Government, and this author’s personal attendance at their annual meetings.
• 1984 First annual meeting of the American Academy of Algology
• 1984 Dilaudid and Dilaudid HP FDA approved (Schedule II drug).
• 1984 A study on slow release oral morphine showed no correlation between analgesia and plasma level of morphine. (Vater M, Smith G, Aherme GW Pharmacokinectics and analgesic effect of slow-release oral morphine sulphate in volunteers Br J Anaesth 1984 Aug;56(8):821-7) <This reinforced the concept of titration to analgesia instead of fixed amount dosing for pain, and justified escalating doses.>
• 1984 A letter to the editor entitled “Pain, the physiological antagonist of opioid analgesics” (GW Hanks, RG Twycross Lancet June 30 1984;1(8392):1477-8) contended that pain itself reduced the effects of analgesics, implying a measure of safety if pain were present during their use.
• 1986 Russell Portenoy and Kathleen Foley published a paper on the use of mainly low dose opioids among 38 non-cancer patients with no reported misuse/addiction. This small study was widely quoted by drug manufacturers and champions of opioid prescribing for the next 25 years as evidence of low addiction risk. Specifically, the authors concluded in the prestigious journal Pain, [25(1986):171-86] “For non-cancer pain, narcotics “can be safely and effectively prescribed to selected patients with relatively little risk of producing the maladaptive behaviors which define opioid abuse.” (Gounder, C. New Yorker Magazine, Nov. 8, 2013)
• 1986 World Health Organization develops their analgesic ladder, including opioids, and encouraged the treatment of cancer pain with opioids
• 1986 Nyswander ME and Dole VP Published a paper “On the use of methadone to limit physical dependence in the treatment of chronic pain” (In: Foley KM, Inturrisi CE, editors. Advances in Pain Research and Therapy. Vol. 8. New York: Raven Press; 1986. pp. 187–190). This article may have promoted the prescribing of methadone for chronic pain. Methadone later turned out to have ten times the rate of death compared to other opioids.
• 1987 MS Contin approved by FDA and was marketed exclusively for cancer pain initially according to the 2003 GAO report on Oxycontin
• 1987 Cephalon founded by Frank Baldino (pharmacologist), Michael Lewis (neuroscience), and James C. Kauer (organic chemist), all three former scientists with DuPont. Cephalon developed Actiq, Fentora, Nuvigil, and Provigil. In 2008 Cephalon paid 425 million to the federal government due in part to marketing Actiq for off label uses. Cephalon was acquired by Teva in 2011.
• 1987 Utah board of medicine established guidelines regarding the use of controlled substances to treat pain
• 1988 Study on hydromorphone blood levels and pain control concluded “Knowing that there is a low concentration of narcotic in the blood of a patient with chronic severe pain who is receiving high drug doses and who shows lack of both efficacy and side effects may reassure health care professionals that further narcotic dosage escalation is appropriate.” MM Reidenberg et al Clin Pharmacol Ther 1988 Oct;44(4):376-82)
• 1988 Forest Tennant, D. Robinson, A Sagherian, and R Seecof published a paper (NIDA Res Monogr 1988;81:174-80) that discusses a systematic clinical evaluation of 52 chronic non-malignant pain patients with a mean age of 49 years, evenly divided male/female, that were referred for treatment of severe intractable pain after having failed several other therapies. “Once pain relief was achieved, patients did not escalate their dosage, and they were able to maintain pain relief for long time periods. Opioids used were different for different patients and had a daily dosage range of hydromorphone 8-120mg, methadone 10-240mg, oxycodone 15-80mg, meperidine 200-2000mg, and morphine 60mg. Although opioids produced dependence in all patients and complications of constipation and edema in about one third, high daily opioid dosage treatment appeared to be the only medical means to achieve adequate pain control in these subjects”. The author measured plasma levels of these drugs and found several of those taking codeine and some taking methadone had no detectable levels of these drugs.
• 1988 Minnesota board of medicine established guidelines regarding the use of controlled substances to treat pain and Virginia established intractable pain policies
• 1988 American Academy of Pain Management founded and later began offering “Certificates in Pain Management” to non-physicians after paying a fee then taking a short written test. This organization changed their name to the Academy of Integrative Pain Management in 2016
• 1988 American Medical Association recognizes Pain Medicine as a specialty and that year the American Academy of Pain Medicine seated its first member in the AMA House of Delegates
• 1989 Massachusetts board of medicine issued guidelines regarding use of controlled substances to treat pain, Texas launched an intractable pain treatment policy
• 1989 Weissman & Haddox created the term “pseudoaddiction” based on their experience with a 17 year old leukemia patient with chest wall pain who appeared to be addicted due to inadequate pain medication. (Pain 1989 Mar;36(3):363-6) This term was later used by opioid manufacturers to promote opioid overuse and by addicts to justify higher doses should be prescribed by physicians. Haddox later became Vice President of Health Policy at Purdue, manufacturer of Oxycontin
• 1989 Review article “Opioids in chronic pain” by HJ Mcquay noted “patients who are prescribed opioids for the management of sensitive pain do not become addicts. To deprive them of this means of pain relief is unjust.” HJ McQuay Br J Anesthes.1989 Aug 63 (2):213-219
• 1989- The term “breakthrough pain” first appeared in the medical literature (Cancer 1989;63:2284-2288), coined by Russell K. Portenoy, M.D., Mathelyn Maldonaldo, RN, Ronald Fitzmartin PhD, Robert F. Kaiko PhD, and Ronald Kanner, MD in an article regarding cancer patients receiving MS Contin for pain. Portenoy was the principle author and published at least 26 other articles regarding “breakthrough pain”.
• 1990- The venerable R. Melzack published “The tragedy of needless pain” in the widely read Scientific American magazine [Sci Am. 1990 Feb; 262(2):27-33.] and this article was considered seminal in enhancing prescribing of opioids for chronic non-malignant pain. In this article he stated: “ Many people suffer not because their discomfort is untreatable but because physicians are often reluctant to prescribe morphine…many care givers, afraid of turning patients into addicts, deliver amounts that are too small or spaced too widely to control pain. Yet the fact is that when patients take morphine to combat pain, it is rare to see addiction.”
• 1990 RK Portenoy and NA Hagen characterized “breakthrough pain”, and published an article about its characteristics. (Pain 1990; 41:273-81)
• 1990 Russell Portenoy and Kathleen Foley along with C. Inturrisi published a paper in Pain 1990 Dec;43(3):273-86 stating “opioids should not be withheld on the assumption that pain mechanism, or any other factor, precludes a favorable response. “….the clinical use of opioids should include dose escalation to maximally tolerated levels and repeated monitoring of analgesia and other effects” “In 1990 Russell Portenoy was quoted in other journal articles advocating for the use of opioids for chronic non-malignant pain (J Pain Symptom Manage. 1990 Feb;5(1 Suppl):S46-62.
• 1990 Fibromyalgia was coined and used to justify the treatment of pain without any objective signs or symptoms, without any known cause or pathophysiology
• 1990 Clinical Journal of Pain established as the American Academy of Pain Medicine’s first official journal
• 1990 Arizona state medical board issued guidelines regarding the use of controlled substances to treat pain and California developed an Intractable Pain Therapy Act, Section 2241.5. California’s policy specifically stated “No physician or surgeon shall be subject to disciplinary action by the board for prescribing or administering controlled substances in the course of treatment of a person for intractable pain” with the exception the patient may not being treated for chemical dependency or with medications used for a non-medical purpose.
• 1990 Duragesic approved by FDA (Schedule II drug) and was used primarily for cancer pain initially. The initial studies in fentanyl patch technology was from Alza, a small pharmaceutical company that began working on the technology in 1984 after developing a commercially successful scopolamine patch.
• 1991 S Schug, A Merry, and R Acland published an article in Drugs [1991Aug;42(2):228-39] stating “Inadequately treated acute and chronic pain remains a major cause of suffering, in spite of enormous advances in pharmacology and technology. Opioids provide a powerful, versatile, widely available means of managing this pain, but their use is too often restrained by ignorance and mistaken fears of addiction. However, problems (such as tolerance, physical dependence, addiction and chronic toxicity), anticipated from experience with animal experiments and pain-free abusers, seldom cause difficulties when opioids are used appropriately to treat pain (so-called 'dual pharmacology'). “
• 1991 Postgraduate Medicine article Morphine myths: sedation, tolerance, addiction was published (67 Suppl 2 S100-2) by M. Zenz who argued “Morphine and other strong opioids are still, more than 180 years after the synthesis of morphine, not adequately used in clinical practice and many patients suffer unnecessarily severe pain in consequence. Governments limit morphine usage by legal restrictions. The underuse of morphine and its restriction in many countries is mostly due to prejudice and myths which clinical experience does not show to be true. Morphine is a very safe drug, correctly prescribed in chronic pain therapy, the only severe side effect being constipation.”
• 1991 Brian Goldman, MD published a paper (CMAJ. 1991 Jun 15;144(12):1660-4.) entitled “Analgesics and chronic pain: “If all you have is a hammer, every disease is a nail” exploring opioid use in chronic non-malignant pain. In this paper, Russell Portenoy is quoted saying about “several large prospective studies that were completed in the 1980s with surprising results: “They concluded that the documented incidence of iatrogenic addiction to prescribed narcotic painkillers was of the order of 4 cases per 10,000 patients. These data suggest that patients with no prior history of alcoholism or abuse or street drugs are at extremely small risk of developing these behaviors when given opiate drugs therapeutically for the treatment of pain.”
• 1991 Oregon and Georgia medical boards issued guidelines regarding the use of controlled substances to treat pain
• 1991 Oramorph FDA approved as a Schedule II drug (Roxane Laboratories)
• 1991 American College of Pain Medicine founded (became the American Board of Pain Medicine in 1994)
• 1992 Russell Portenoy published an article “Chronic Opioid Therapy for Non-Malignant Pain: From Models to Practice” (APS Journal later known as Pain Journal 1992;1(4):285-88) In this journal he fully makes the transition from treatment of cancer pain to non-cancer pain with opioids. “The general applicability of a biopsychosocial model of chronic pain might lead to the expectation that some patients with nonmalignant pain respond to opioid therapy in a manner that mirrors the typically favorable response of the cancer pain patient, just as some patients with cancer pain demonstrate psychological disturbances and disabilities reminiscent of a severe chronic nonmalignant pain syndrome. The most reasonable approach is probably one that is commonly accepted for other inadequately studied analgesic treatments, namely, empirical patient selection followed by a therapeutic trial. The concept of the therapeutic trial has not been applied to the use of opioids for chronic nonmalignant pain, despite the lack of any compelling reason to avoid the approach.” Portenoy goes on to critique the guidelines for opioid prescribing for chronic non-malignant pain created by Dr. Chabal and colleagues, who advocated of only one formulation of a single opioid drug, inform their patients ‘the more you take it, the less it works’, and that additional medication requests are automatically refused suggesting the patient has a drug problem. Portenoy argues for “flexibility” in opioid use, that there is “evidence in the clinical literature analgesic efficacy seldom declines over time unless there is worsening in the underlying pathology”, and that requests for higher doses may have multiple causes including pseudoaddiction, tolerance, worsening underlying pain in addition to addiction. He also notes Dr Chabal neither mentioned a therapeutic trial nor a “treatment holiday”, and there was no discussion of the “need for sophistication in opioid pharmacotherapy”.
• 1992 Russell Portenoy and R Payne published a chapter “Acute and chronic pain in “Comprehensive Textbook of Substane Abuse” Baltimore: Williams Wilkins 1992;714 in which 25,000 pain patients treated with opioid narcotics were reviewed and found only 7 demonstrated a “true addictive lifestyle” with the risk of true addiction 0.3% of the population suffering with chronic non-malignant pain.
• 1992 E. Richard Blonsky, MD became president of the American Academy of Pain Medicine
• 1992 Zenz, Strumpf, and Tryba published a paper describing long term treatment of 100 patients with opioids for chronic pain (J Pain Symptom Manage 1992 Feb;7(2):69-77) with morphine (daily dose mean 255mg with a range of 20-2000mg/day) stating 51% received good pain relief, 28% partial pain relief, and 21% did not have good pain relief in a mean 7 month treatment period. Functional improvement was directly correlated to reduction in pain. They also concluded there was no cases of addiction and no side effects other than nausea and constipation, and “Our results indicate that opioids can be effective in chronic nonmalignant pain”
• 1992 Colorado developed an intractable pain treatment policy
• 1992 the Agency for Health Care Policy and Research developed a policy on the assessment of post-operative pain stating “opioid analgesics are the cornerstone of pharmacological postoperative pain management” and “psychological dependence and addiction are extremely unlikely to develop after patients without prior drug abuse histories use opioids for acute pain”. They also stated initial postoperative dosing should be on a scheduled basis rather than prn, then later may use Q4H prn dosing. <the encouragement of post op pain opioid dosing by physicians ultimately led to chronic use and an increase in the rate of addiction>
• 1992 First board certification of physicians practicing pain by the American College of Pain Medicine
• 1992 First board certification of pain physicians by the American Board of Anesthesiology- hundreds of doctors from 1992-1998 without any formal pain training at all were certified by the board as having “Specialized qualifications in pain management” after taking a written test. Hundreds of physicians could now claim “board certification in pain medicine” without training, opening up a pandora’s box of opioid prescribing.
• 1992 American Academy of Pain Medicine incorporated in Illinois
• 1993 Oralet (fentanyl solid sweetened “lollipop” lozenge was released by Abbott Laboratories as a Schedule II drug for preoperative drug sedation in children in the hospital setting and for treatment of painful procedures in adults and children. It was developed beginning in 1985 by Theodore H Stanley with clinical trials beginning in the late 1980s. Janssen declined to bring it to FDA approval so another company was formed, Anesta to develop oral transbuccal fentanyl citrate. During pre-approval clinical trials with Oralet, Drs. Perry Fine and Michael Ashburn contemplated the use of the drug in cancer patients for break through pain, a term championed by Portenoy. Oralet was later withdrawn due to nausea from the drug. The blood levels achieved were much lower than the later released Actiq and Fentora.
• 1993 Alaska, Texas, and Wyoming state boards of medicine issued guidelines regarding the use of controlled substances to treat pain and Washington issued an intractable pain treatment policy
• 1993 First ACGME accredited pain fellowships beginning with approximately 35 programs. These programs from 1993-2000 were taught by mainly by anesthesiology faculty, doctors that primarily were operating room or labor pain doctors at the time. “As a result, many new pain specialists were intellectually or clinically unprepared by their formal training to assimilate the burden of managing chronic pain” (Bonica’s Management of Pain by Scott Fishman published 2012 p. 1560) The first multidisciplinary requirements for fellowship training in pain medicine were not implemented until 2006 implying many doctors trained in fellowship before that point potentially had inadequate training in chronic pain management. Bonica, the father of pain medicine recognized the need for a multidisciplinary approach in 1947
• 1993 Purdue launched Partners Against Pain according to a website, a program designed to connect patients with pain management therapies including opioids. The Partners Against Pain website contained many articles with misinformation, attempting to downplay the addictiveness of opioids and overstating their safety (https://www.fda.gov/ohrms/dockets/dockets/01n0256/c000297-A.pdf)
• 1994 Robert N Jamison PhD, Karen O. Anderson PhD, Christine Peeters-Asdourian MD, and Michael F. Ferrante MD published a paper “Survey of opioid use in chronic nonmalignant pain patients” Regional Anesthesia Jul-Aug 1994;19(4):225-30 Two hundred seventeen patients being treated for pain at two pain centers completed a questionnaire, and one hundred twelve were taking oral opioids for pain. Of those taking opioids, 83% felt that opioids were moderately beneficial in relieving their pain, 25% believed the opioid had not lost its ability to relieve the pain over time, and 35% reported no need to increase their medication. 36% expressed no fear of addiction or dependence, and 56% had no unwanted side effects.
• 1993 American Academy of Pain Medicine inaugurates its Comprehensive Review Course in Pain Medicine
• 1994 the International Association for the Study of Pain defined chronic pain as a clinical entity distinct from acute pain or “pain”.
• 1994 the Agency for Health Care Policy and Research developed a policy on the assessment of cancer pain.
• 1994 California Board of Medicine adopts guidelines for opioid prescribing: Except for gross negligence, “A physician and surgeon may prescribe for, or dispense or administer to, a person under his or her treatment for a medical condition dangerous drugs or prescription controlled substances for the treatment of pain or a condition causing pain, including, but not limited to, intractable pain. (b) No physician and surgeon shall be subject to disciplinary action for prescribing, dispensing, or administering dangerous drugs or prescription controlled substances in accordance with this section." Alabama state medical board issued guidelines regarding the use of controlled substances to treat pain and Florida issued a pain treatment policy for intractable pain.
• 1995 the American Pain Society conducted a quality improvement oriented literature review on the treatment of acute and cancer pain concluding: (a) a report of unrelieved pain raises a “red flag” that attracts clinicians’ attention (b) making information about analgesics convenient where orders are written (c) promising patients responsive analgesic care and urging them to communicate pain (d) implementing policies and safeguards for the use of modern analgesic technologies; and (e) coordinating and assessing implementation of these measures (JAMA 1995 Dec 20;274(23):1874-80)
• 1995 December 12, the FDA approved Oxycontin (Purdue Frederick Pharma) in dosages of 10, 20, and 40mg “for the treatment of moderate to severe pain lasting more than a few days”. The 80 and 160mg tablets were approved later. The highest dosage tablet was equivalent to 24 tablets of 10mg hydrocodone or 48 tablets of 5mg hydrocodone.
• 1995 Idaho state medical board issued guidelines regarding the use of controlled substances to treat pain, and Missouri, Oregon, and Nevada issued an intractable pain treatment policy. (
• 1995 The American Pain Society introduced the concept of pain as a vital sign in a November 1995 presidential address of James Campbell, MD, not as a directive. Dr. Campbell stated “Vital signs are taken seriously. If pain were assessed with the same zeal as other vital signs are, it would have a much better chance of being treated properly. Quality care means that pain is measured and treated.” (Campbell JN. APS 1995 Presidential address. Pain Forum. 1996;5:85–8)