Drug historians David Courtwright and Virginia Berridge have shown how political elites in the USA and Europe in the late nineteenth and early twentieth centuries came to view and define non-medical narcotic use as a problem that governments needed to regulate [41,42]^[1][2]. Authorities on both sides of the Atlantic were struggling with the overconsumption of opiates in the period 1880–1920, but the impact of the opiate crisis was felt most dramatically in the US with an exponential rise in the number of morphine, heroin and cocaine addicts in the 1890s [43]^[3]. Under American leadership, diplomats worked on an international drug control regime; starting with the Hague Convention of 1912, they sought through international conferences and treaties to prohibit the non-medical use of narcotics and control the supply chains [44]^[4]. They called for stricter regulations to enable maximum legislative control with doctors and druggists as gatekeepers of narcotic drugs [45]^[5]. The Harrison Act in the United States (1915) aimed also at limiting the medical use of opiates and thus curbing consumer demand, followed by similar restrictive opiate legislation in other countries. There were penalties for pharmacists, doctors and addicted patients who infringed the laws, and for any party without legal permission importing or exporting narcotics [46]^[6]. The new prohibitive international regime would leave a hole in family medicine cabinets in the USA and Europe [39]^[7]. Doctors and lay consumers in search of prescription medicines with sedative, hypnotic and pain-relieving properties did not have to wait long before alternative drugs would be available. The burgeoning international pharmaceutical industry started developing new generations of prescription-only chemically synthesized sedatives, hypnotics and painkillers. The foundations were thus laid for the emergence of a new mass market for prescription-only, psycho-active and pain-relieving medicines under the supervision of doctors and pharmacists [47]^[8].

2. Regulating New Addictive Wonders for the Doctor’s Bag

The public appetite for more potent, faster-acting and safer hypnotics, sedatives and painkillers continued to grow. German, British, French and American pharmaceutical companies did their utmost to meet these relief demands with ambitious drug screening programs [48]^[9]. While the Canadian judge Emily Murphy issued an early warning against the use of these new psychoactive compounds, stating that ‘anything that acts like an opiate IS an opiate’, a new analgesic and cough medicine oxycodeinon (oxycodone) under the tradename Eukodal was launched in 1919 by German pharmaceutical company E. Merck (Darmstadt) [49,50]^[10][11]. The name Eukodal was intentionally chosen to differentiate the drug (in marketing terms) from conventional opiates and to associate it with the family of barbiturates that was still officially considered to be non-habit forming [51]^[12]. Doctors were made to believe that this new, more potent pain medicine could be used without special precautions and among other therapeutic uses (analgesic, narcotic, cough medicine) as an antidote against morphinism [52,53]^[13][14]. Eukodal was introduced into a drug market saturated with sedatives, hypnotics and stimulants, which were available in dozens of formulas and brands. The relatively high price of the new prescription drug also limited its use [54]^[15]. In the late 1920s and early 1930s, warnings about addiction (‘Eukodalism’), intoxication risks and counterfeit prescriptions began to circulate in European medical and pharmaceutical journals [55,56,57]^[16][17][18]. In response, the regulatory authorities across Europe and the USA labeled Eukodal as an opiate medicine with restrictive prescription rules [58]^[19]. With the expiration of the oxycodone patent, Eukodal gradually disappeared from the medical market in Europe, surviving only temporarily in the form of unnecessary war supplies that ended up in the criminal narcotic trade [59]^[20]. The international production, distribution and use of opiates was further restricted after the Second World War. Supply control was dominant, with a reduction in the nonmedical markets sought through curtailing and monitoring of excess capacity for the medical markets of opium producers and narcotic drug manufacturers. Regulation to avoid abuse was deemed essential, but overly stringent regulation that prevented patients from pain relief caused them to seek alternative means of obtaining these drugs and that had likewise to be prevented [60]^[21] (p. 145). The driving force behind the tightening of the international prohibition regime and the focus on supply was Harry J. Anslinger, the head of the US Federal Bureau of Narcotics (FBN). He played a crucial role in the US-led war on drugs by simplifying the existing increasingly unwieldy drug control machinery and persuading the United Nations in taking the lead to develop a unifying and uniform international prohibition-oriented treaty. The resulting 1961 United Nations Single Convention on Narcotic Drugs came indeed close to imposing an international prohibition regime for narcotic drugs. Addiction to narcotic drugs was presented in the treaty as a ‘serious evil for the individual’ that is ‘fraught with social and economic danger to mankind’ [25]^[22]. A key provision of the Convention imposed the obligation to all international parties to take such legislative and administrative measure ‘to limit exclusively to medical and scientific purposes the production, manufacture, export, import, distribution of, trade in, and possession of narcotic drugs’ [25]^[22]. In addition to addressing control issues, the Convention obligated countries also to work towards adequate medical access to narcotic drugs to alleviate pain and suffering, but that would prove rather difficult. As a safeguard to limit the use of narcotics, the international Narcotics Control Board (INCB) was set up to monitor the global production and distribution chains in order to prevent the medical and non-medical supply chains from playing off one another. The Convention marked a significant change in the national policies regarding legal barriers in accessing opiate medicines. Across the world, amplified by a wave of opiophobia, stricter control measures in national policies and legislation were implemented further impeding access to legitimate medical use of opiate medicines [60]^[21] (p. 146). In most European countries, the prescribing of morphine-like controlled substances would require a permit to prescribe or receive opiates, multicopy prescription requirement on special forms and limitations on the treatment period and on the dispensing privileges. The resulting far-reaching control measures would for decades cast a shadow on the adequate access to the steadily growing bag of controlled narcotic medicines for medical and scientific purposes [61]^[23]. Underprescription of opiates became the rule in the USA and most other countries [62]^[24]. The focus of the supply-side drug control regime was more on non-Western plant-based narcotic drugs and less on the new generations of psychotropic products of the Western chemical and pharmaceutical industries. The latter succeeded in meeting market demands by formally avoiding the international drug control regime in the 1950s and early 1960s. This is exemplified by the industrial product wave of hypnotics (e.g., barbiturates and benzodiazepines), sedatives (e.g., meprobamate) and stimulants (amphetamines) for inducing sleep, soothing nerves and brightening Cold War-infused anxious moods [36,63]^[25][26]. Medical morphine use might have dwindled but addiction on prescription continued in an ‘upper’ and ‘downer’ pill disguise [47]^[8]. In addition, the over-production and over-supply by the pharmaceutical industry of these medical stimulants and sedatives fed into global illegal markets [39]^[7].

3. Unforeseen Consequences of a New Dosage Form

Morphine as a palliation medication survived the ‘opiaphobia’ and ‘morphinophobia’ which continued to circulate in pain specialist quarters in America and Europe [68,69,70,71]^{[27][28][29][30]}. Most specialists in the 1970s advocated for multidisciplinary pain treatment programs involving physical therapy, psychotherapy and additional pharmacological therapy in the form of the new generation of nonnarcotic analgesics (e.g., non-steroidal anti-inflammatory drugs, NSAIDS such as ibuprofen) and psychotropic drugs. An intensified war on drugs during the Nixon era raised the regulatory stakes once again for American doctors prescribing narcotic relief-bringing drugs for their patients [72]^[31]. Undertreatment of cancer pain and chronic pain became the rule rather than the exception in the 1970s and 1980s [73]^[32]. With the exponential growth of surgical interventions and the steep rise in cancer cases, a pain crisis was in the making [74]^[33]. The development and introduction of a new formulation technology—sustained- or slow-release dosages that were characterized by releasing specific active drug compounds into the body over an extended period—changed pain medicine and the opioid concerns in medicine for the better (handling undertreatment) and for the worse (inducing overtreatment). In the 1970s, the Scottish drug producer Bard Laboratories introduced this technological innovation into the burgeoning field of pain medicine [75]^[34]. In 1980, the producer obtained an English license for selling a sustained-release preparation of morphine under the brand name MST [76]^[35]. MST was marketed as a revolutionary step in the transition of cancer pain treatment from pain relief to pain management. MST was initially considered a niche market product for palliative care within the growing field of end-of-life hospice care [77]^[36]. The Reagan era of deregulation and continuing liberalization of the medical marketplace, with more liberal direct-to-consumer advertising regulations of drugs, created a fertile ground for post-marketing expansion of the MS-Contin medical market [78]^[37]. Without strong political support of the Reagan administration, the weakened and overburdened FDA regulators, faced with pressure from cancer patients and doctors mobilized by Purdue, ultimately accepted the novelty claim. They acknowledged the product claim that this new drug formulation significantly reduced the risk of addiction and overdose in pain management with regard to morphine as a schedule II narcotic [30,79]^[38][39]. Purdue Pharma subsequently turned MS-Contin into one of its new cash cows within the growing market of oncological pain management. The financial support by Purdue Pharmaceutical of the leader in the field of oncological pain management, Russell Portenoy (from the world-renowned Memorial Sloan Kettering Cancer Center), proved paramount in mobilizing medical support for MS-Contin [80]^[40]. With his radical opioid-based pain management approach to chronic pain (both malignant and non-malignant), Portenoy took to the medical lecture circuit and published a series of articles [81,82]^[41][42]. He argued that, as long as patients had no history of drug abuse, the addictive risk of using opioids was very low [82]^[42]. His pain management movement gradually gained ground among medical opioid advocates, who engaged with a generation of American physicians with a low level of professional education about addictive substances [83,84]^[43][44]. This spurred Purdue management to develop a more potent pain medicine, one with morphine-like qualities but without morphine’s phobic image, that could be used to achieve a significant growth in the market of chronic pain management [85]^[45]. Similar to Merck’s German management’s approach in the 1910s, the search was for an opiate-like compound that people would not associate with the stigma of morphine but that had similar therapeutic qualities. Oxycodone was lying idle on a shelf waiting to be invigorated again as part of a third drug life cycle as a follow up on Endo laboratories’ successful Percodan and Percocet low-dose oxycodone aspirin/acetaminophen analgesic combination products. Though in the early 1970s the US government had classified oxycodone as a schedule II opiate drug, this did not prevent it from being ‘rediscovered’ by Purdue scientists. In imitation of MS-Contin, they reformulated oxycodone in the form of a slow-release pain medicine with proclaimed low addiction and overdose risks [86]^[46]. The FDA accepted the novelty claim without strong opposition and approved the new drug under the trade name Oxycontin^® in 1995 for chronic cancer pain, thereby making it available as a ‘scheduled narcotic’ for prescription to all US doctors and their patients [87]^[47]. The FDA’s European counterpart—the EMA—handled the Oxycontin registration dossier in a similar fashion and advised the European Commission to grant market approval of this narcotic drug for the indication chronic cancer pain without additional registration requirements [88]^[48]. Extra precautions such as strong addiction warnings in the medicine leaflet were not judged necessary by either regulator for introducing the narcotic on the medical market. Thus, while both the FDA and EMA fulfilled their duties in terms of product regulation, in terms of the also much-needed regulation and monitoring of marketing and health care practices, both agencies at the time did not have sufficient executive powers. It would last more than a decade before these shortcomings were repaired by the enactment in 2010 of the New EU Pharmacovigilance Legislation and in 2012 the FDA Safety and Innovation Act [89,90]^[49][50]. In the meantime, with insufficient pro-active vigilance of the regulatory systems, the potential for harm was significant [91,92]^[51][52]. Purdue’s marketeers would start challenging FDA and EMA’s rather narrowly defined chronic cancer pain therapeutic drug indication for Oxycontin. In aiming at a swift expansion of the indication range towards the far more common non-cancer types of pain, they built on the legacy of the marketing genius and co-founder of Purdue—the American physician Arthur Sackler—who turned tranquillizers like Librium (chlordiazepoxide) and Valium (diazepam), known as benzodiazepines or ‘benzos’, into staples in any American medicine cabinet [76]^[35] (pp. 48–52). This involved skillfully promoting the new Oxycontin drug directly to the community of health professionals through a number of means, including: glossy multipage color advertising in leading medical journals; publishing medical newspapers filled with promotional material and dubious paid-for scientific studies that exaggerated the problem, downplaying side effects and advocating new conditions for which the drugs would work; hiring thousands of doctors to promote the drugs (key opinion leaders or KOLs in the jargon); maintaining close relationships with FDA regulators; and monitoring doctors’ prescription behaviors through the prescription-tracking company IMS (Intercontinental Medical Statistics) [96]^[53]. As such, Purdue’s marketeers were able to take maximum advantage of the post-Reagan era of increasing entanglement of medical knowledge production and financial interests between drug companies, doctors and hospitals in the USA [97,98,99]^[54][55][56].

4. An Opioid Addiction Crisis in the Making: The First US Wave (1998–2010)

The closer ties in the 1990s in the USA between big pharma and the health care system played an important role in stimulating Oxycontin and other ‘new’ opioid consumption [104,105,106,107,108]^{[57][58][59][60][61]}. Alongside the fast-growing movement of pain treatment patient advocates, Purdue marketers portrayed pain medicine as a backward area in medicine that needed a radical change, not only in cancer pain centers but also in general practice and for chronic pain as well [109,110]^[62][63]. Purdue pharma and other opioid producers in conjunction with medical journals supported post-academic courses that paid increasing attention to the recognition, diagnosis and treatment of pain. The idea was planted that doctors under-treated pain, and that the treatment of pain was a ‘fundamental human right and duty’ [111]^[64]. Prescription monitoring of narcotic drugs was being portrayed as frustrating the efforts to modernize pain medicine and undermining the autonomy of doctors. The overall message was that pain must be treated, preferably with a new generation of slow-release opioid drugs with a negligible risk of iatrogenic addiction [112]^[65]. However important the impact of this aggressive kind of pain management mongering might have been, it still depended on physician and consumer support and regulatory failure to be successful. In the decade of public optimism about uncovering the secrets of life in both the human genome and the brain, the promise of fast pain relief was embraced in the consultation room [116]^[66]. This resulted in pain being included as a fifth vital clinical sign that needed treatment. The American Pain Society and the American Academy of Pain Medicine issued a consensus statement endorsing opioid use for chronic non-cancer pain [117]^[67]. State medical boards and state policies started to relax regulations about prescribing opioids to non-cancer patients [118]^[68]. In support of these relaxing opioid prescription policies, the American Medical Association seemed to be too optimistic about physicians’ professional role as opioid gatekeepers [104]^[57] (pp. 62–64). Furthermore, changing quality standards for hospital care and the rise of polyclinic or outpatient surgery, in combination with the professional support of pharmacological pain treatment programs and the existence of unmonitored opioid pharmacies (so-called pill mills), have also played an important role in the growth in consumption of opioid painkillers [121]^[69]. Hospitals are required to measure their quality of care and pain is one of the indicators that determines quality. The results of these quality measurements are made public, and hospitals advertise these figures for marketing purposes. The less pain that patients experience, the higher the hospital’s rating [122]^[70]. . Growing focus on pain management meant growing opioid sales, with direct-to-consumer ads by Purdue Pharma, like ‘Oxycontin: It gets you high’ or ‘I couldn’t get through the day without it’ in the USA [124]^[71]. There was a definite racial subtext to the Oxycontin ads, which targeted primarily Caucasian white consumer groups that were not thought to be at risk of addiction (i.e., suburban and rural non-Hispanic white populations). Counties with a higher degree of rurality appeared to have higher opioid prescribing rates and this association could be explained by higher percentages of whites, higher unemployment rates, less nurse practitioners and physician assistants and more specialized opioid prescribers such as surgeons and oncologists [125]^[72].  Hospitals and health insurance plans were largely in support of the new pain management programs that included chronic pain management (e.g., for musculoskeletal pain problems), in addition to acute pain (cancer and post-operative). Opioids were indiscriminately promoted for both types of pain management, despite lack of evidence of the effectiveness of prolonged opioid use in the case of the most frequent chronic non-cancer pain [126]^[73]. Between 1999 and 2010, the medical sales of opioids in the USA quadrupled. Following Purdue Pharma, other drug companies like Endo Pharmaceuticals (DuPont), Abbott, Johnson and Johnson’s Jansen Division and the generics companies Mallinckrodt pharmaceutical and Teva’s Malvern-based Cephalon unit jumped on the slow-release opioid bandwagon with oxymorphone (Opana^®, a Normorphan make-over), hydromorphone (Dilaudid^®), tapendatol (Nucynta), oxycodone (Roxicodone^®) and fentanyl (Duragesic^®, Actiq^® lollipop, Fentora^®) [127]^[74]. All these companies, Purdue Pharma included, used the opium alkaloid thebaine as the key chemical precursor for the production of semi-synthetic opiates, except for fentanyl and tapendatol which are synthetic opioids. Around the early 1990s, plant biologists at the Tasmanian Alkaloids facility (Johnson and Johnson subsidiary), together with professor Meinhardt Zenk, succeeded in genetically modifying the opium poppy Papaver somniferum to produce a morphine-free poppy plant variety containing high thebaine concentrations [128]^[75]. This catapulted the highlands of Tasmania into the nucleus of the global opioid supply chain, with a more than 50% share of the global thebaine supply [129]^[76].

5. The Second (2010–2014), Third and Fourth Wave of the Opioid Crisis

From 2010 onwards, the second wave was associated with rapid increases in heroin-related overdose deaths and a shift youthwards. This coincided with the increased controlling and monitoring of the legal access to prescription opioids and the introduction of an abuse-deterrent formulation (ADF) of OxyContin by Purdue Pharma, that made it difficult to abuse the drug in this fashion [135]^[77]. Criminal entrepreneurs and networks fulfilled the needs of large numbers of prescription-opioid-addicted patients, who either no longer had access to medical market sources due to more stringent prescription regulations, had insurance challenges or were dissatisfied with the new abuse resistant oxycodone pills. Mexican transnational criminal organizations, which from the 1990s controlled most of the US illegal drug markets, sensed a fast-emerging new market in the USA [136,137]^[78][79]. They began to aggressively supply massive amounts of cheap heroin to partner criminal groups and gangs in the United States. American consumers by the hundreds of thousands resorted to these non-medical black-market opiate channels. Heroin became widely regarded by iatrogenic-opioid-dependent US users as a suitable and cheap black-market alternative for the opioid pain relievers [138]^[80].

In the third (2014–2019) and current fourth wave (2019–) of the crisis, the further increase of opioid use and overdose death rates were associated with Chinese-manufactured, cheap and extra-strong synthetic opioids such as fentanyl and fentanyl analogs (e.g., the most dangerous fentanyl derivative is carfentanyl) as well as the combination of psychostimulant drugs and opioids, which are primarily distributed via the existing non-medical criminal channels [139,140]^[81][82]. During the third and fourth waves, the opioid epidemic spread quickly to US communities both on the east and west coast that were initially hardly affected, including African American, Hispanic and other ethnic minority groups [132,141]^[83][84]. Existing inequalities within society related to socioeconomic status and race have become increasingly important in the third and fourth wave of the opioid crisis. Three clear factors for overdose deaths are currently: coming from a deprived background, being from a racial or ethnic minority group and being part of the 1981–2000 millennial generation [142,143]^[85][86].

National and local efforts to deal with the opioid epidemic have been on the rise. Possession of illegal drugs and the illicit use of legal drugs are still US federal crimes and prisons are still filled with convicts convicted of these crimes [144]^[87]. But, according to the former editor-in-chief of the New England Journal of Medicine Marcia Angell, many states, counties and cities in the USA have begun to regard opioid addiction more as an issue of public health than of criminal justice [79]^[39]. As part of a new harm reduction approach, centers are being opened in which people who seek help are treated with opioid replacement therapy (e.g., methadone and buprenorphine (Subutex)— a method known as ‘medication-assisted treatment’ or MAT). Naloxone (Narcan), the antidote for an opioid overdose (opium antagonist), is now sold over the counter as an emergency kit in almost all US states. If used immediately and properly, it can prevent an otherwise inevitable death from a drug overdose. It is also becoming more common for some drug courts to drop criminal charges in return for an agreement to submit to treatment and monitoring [79]^[39]. 

The volatile politics of drug regulation both nationally and internationally continue to mold the US opioid crisis that started as an iatrogenic epidemic but developed into an illicit-opioid-fueled crisis that is currently dominated by trafficking fentanyl and fentanyl analogs that are primarily produced in Asia. According to Brookings Institute researcher Vanda Felbab-Brown, there is no easy way out due to the lack of ‘global political appetite for scheduling a vast number of dual-use (medical/non-medical) chemicals’, and the rather tense bilateral relationship between the US and China is not of any help [147,148]^[88][89]. The opioid epidemic is not only rampant in the United States. Canada is facing a similar crisis, driven by both prescription and illegal opioid use, with significant overall increases in opioid-related deaths and a marked increase in fentanyl-related deaths in some provinces [149]^[90]. Prescription opioid use also appears to be an early driver of the Canadian crisis, while the increasing availability of opiates and opioids on the illegal market is likely driving the most recent rise in deaths in most Canadian jurisdictions [150]^[91]. In addition, on the other side of the Atlantic, there are also signs of an emerging iatrogenic driven epidemic, albeit in a more silent and nuanced fashion. In Europe, the medical use of opioids has substantially increased since 2009 [151]^[92]. However, the situation in Europe differs significantly from the USA and Canada. Specifically, the regulatory and health insurance contexts and approaches to opioid medicine marketing and prescribing are rather different in Europe. In Europe, direct-to-consumer advertising by pharmaceutical companies is not allowed, so-called pill mills do not exist and most citizens have adequate health insurance coverage and feel no need to search for alternative sources of narcotic drugs. Furthermore, most European countries have vertically integrated healthcare systems facilitating effective control of opioid prescribing. National and local formularies play an important role in restricting availability and limiting the circumstances under which opiates can be used. Moreover, there are multiple legal barriers to accessibility. All of the East European countries and some of the West European countries (e.g., France, Greece, Portugal) require that opioids be prescribed using duplicate or triplicate prescriptions. In most of these countries, special forms must be used which, in some cases, physicians need to purchase [152,153]^[93][94]. Finally, the European health care systems are organized differently with a different reimbursement structure, patient satisfaction monitoring and pharmaceutical price regulation [154]^[95]. Together, this leads to more administrative burden and less incentive to prescribe opioids than in the US, resulting in less opioid use. But they should also be aware that the spiraling of medically controlled licit (‘on prescription’) drug markets and criminally controlled illicit drug markets might have their own uncontrolled future dynamics.