OXYCONTIN: THE POLITICS, SCIENCE, AND SENSATIONALIZATION OF AN ABUSABLE PHARMACEUTICAL

by
Professor T

- TABLE OF CONTENTS -

INTRODUCTION

THE SCIENCE OF OPIOIDS

Opioids Background Information

Scientific Basic

Modern Use

Oxycodone

Abuse Liability

OxyContin

OXYCONTIN AND THE MEDIA

The Media

OXYCONTIN ABUSE

Drug Abuse

Emergency Room Visits

OxyContin Related Deaths

THE DEA AND DIVERSION

The DEA

Illicit OxyContin

FEDERAL HEARINGS AND LAW ENFORCEMENT

Congressional and Public Hearings

Enforcement and Prevention Efforts

Opioid Policy and Practice

THE OXYCONTIN BUSINESS

The Pharmaceutical Industry

The Marketing of OxyContin

Purdue Response and Public Relations

Prescription Monitoring Programs

LEGAL AND SOCIAL ISSUES

Legal Cases

The Fallout

CONCLUSION

- INTRODUCTION –

This is the story of OxyContin, a schedule II opioid pain reliever introduced in 1996 which was more widely abused after its introduction that any prescription drug in the past 20 years. Sales of the drug, marketed by Purdue Pharma, rose to over $1 billion in less than five years, making it one of the fastest growing and highest grossing pharmaceuticals in recent times. Along with its popularity and rapid growth came widespread abuse, attracting attention from the media, the Food and Drug Administration, the Drug Enforcement Administration, Congress, law enforcement officials, and the medical community. Heralded as a highly effective groundbreaking new medication, OxyContin brought relief to millions of chronic pain patients, but also brought suffering and death to drug abusers. The backlash from this was felt by the manufacturer, the medical community, and legitimate pain patients who suddenly found themselves labeled as addicts and unable to obtain medication. The appropriateness of long-term opioid use was brought to the forefront of debate among medical professionals, and the progress which had been made during the past decade in the aggressive treatment of chronic pain conditions appeared to take a step backwards.

To understand OxyContin, one must first know something of the history of opioids, which derive from the opium poppy known botanically as Papaver somniferum first cultivated by humans circa 3400 B.C. From the opium poppy morphine was created, and then in 1898 Bayer released the most famous drug brand of all time, Heroin. A wide variety of opioids were created over the next century, including oxycodone, the active ingredient in OxyContin.

All opioids have in common an unrivaled pain relieving efficacy without toxicity to the body, allowing their use in large quantities over long duration. Unfortunately, opioids also bring euphoria and pleasure to many of their users, leading to widespread use and abuse. Modern science is still unable to separate the euphoric and pain-relieving qualities of opioids, making their use controversial and requiring restrictions on their availability. Longer term opioid use leads to tolerance as well, requiring users to take larger quantities over time to achieve the same initial effects.

OxyContin was unique in that it was available in slow-release 12 hour high-dose formulations, giving physicians to ability to indefinitely increase patient dosage and maintain continued pain relief. Oxycodone seemed to have a lower number of side effects compared to other opioids, but also seemed to produce a uniquely enjoyable euphoric quality and was easily abused because of the high potency of the pills.

The story of OxyContin was in a large part created by the media, which brought national attention to the drug with a wave of sensationalized news stories which began in early 2001. OxyContin was proclaimed a national epidemic and called the ‘New Crack’ with a ‘heroin-like’ high, supposedly claiming hundreds of lives yearly. These claims were not borne out by fact, but the news media was undeterred, and devoted a startling amount of attention to the drug in a 6 month period. This gave the DEA, Congress, the FDA, and the medical community no choice but to respond to these claims.

In truth, abuse of prescription drugs had been occurring for decades. An analysis of prescription drug abuse data showed that OxyContin was responsible for less than 1.0 percent of total drug abuse emergency department mentions. It had also contributed to less than 20 percent of all opioid abuse mentions, and was in fact overshadowed by established opioids such as Vicodin, Morphine, and Percocet. A review of the coroner’s toxicology reports also suggested that the death numbers reported by the media may have been dramatically overstated, and that many of the OxyContin overdose victims had consumed alcohol, anti-anxiety drugs such as Valium, and other opioids.

The Drug Enforcement Administration had already begun to investigate OxyContin diversion and abuse on a small scale in 1999 and 2000, but as the media coverage hit in 2001 and congressional hearing appeared imminent, the DEA drastically stepped up its rhetoric and its investigation of physicians. Before a congressional subcommittee in August 2001, the director of the DEA made it clear that OxyContin was the agency’s number one priority, characterized as a societal threat unlike any which had been seen for decades. Within six months, the DEA requested a budget allocation of $25 million to combat OxyContin diversion and abuse on top of the $114 million it was already requesting for its Diversion Control department.

The diversion of OxyContin was due to its high street price; approximately $1 per milligram, nearly 10 times the pharmacy price. Stories were frequently reported about corrupt doctors making thousands of dollars through liberal prescription practices. Legitimate patients were sometimes selling their medication to supplement their income, and people were importing the drug from Mexico and Canada. Originally only popular in certain rural areas, the drug seemed to spread to urban areas as the intense media coverage brought it to attention, and the DEA predicted that the plague was heading west.

Congressional subcommittees were convened to discuss the issue and the company was called on to address the problem. The DEA announced a National Action Plan to combat diversion and abuse through coordination of law enforcement agencies, cooperation with the manufacturer, public education campaigns, and discussions with physician and patient groups. Unsurprisingly, these groups were largely unreceptive because they had been hard at work throughout the decade passing legislation and changing medical opinion to support the increased use of opioids in treating a wider variety of chronic pain conditions. They knew that with increased scrutiny would come a constriction of legitimate use from doctors who feared the threat of DEA investigations. No matter how often the DEA stated that it gave full support to doctors who used opioids appropriately, it was never exactly clear what the DEA’s interpretation of ‘appropriate use’ meant, so physicians were left to look out for their own interests.

It began to appear that partial responsibility for the problem lay with Purdue’s aggressive marketing of the drug. Sales grew from $300 million in 1996 to $1.49 billion in 2001 in part because of Purdue’s targeting of physicians who were already liberal prescribers. Some began to suggest the Purdue had downplayed the risks of the drug by claiming that it had reduced addiction liability due its slow-release mechanism. In also may have been marketed for a wider range of conditions than was appropriate. In 2001 Purdue began to make some effort to combat the problem by withdrawing the highest dose formulation and conducting anti-prescription drug abuse advertising campaigns. Under DEA pressure, the warning label and indications were changed in 2001 to convey the risks of the drug and the appropriate patient populations.

In the face of rising criticism of its practices and calls to withdraw the drug, Purdue remained defiant, claiming innocence and placing the blame fully on those who chose to manipulate doctors and abuse the drug. While publicly proclaiming support for prescription monitoring programs and giving the state of Florida $2.1 million to establish its own monitoring program in exchange for halting an investigation, Purdue quietly opposed other attempts to create or strengthen monitoring programs. A rising tide of legal cases also began to occupy Purdue as patients filed suit against the company for inappropriate labeling and misleading marketing.

As media attention began to subside, OxyContin was still on the radar of the DEA and Congress. After having caught the few corrupt doctors, the DEA settled for frightening the rest into changing their prescribing practices. The doors of clinics began to close and physicians became reluctant to prescribe the drug. It was this change in the medical community’s comfort with opioid use which was perhaps OxyContin’s most tragic legacy. While many doctors simply switched to other possibly less effective opioids, some stopped prescribing altogether. Patients’ advocacy groups found their cause had been set back dramatically, and legitimate chronic pain patients often found themselves unable to obtain treatment.

- THE SCIENCE OF OPIOIDS -

Opioid Background Information

The opium poppy, known botanically as Papaver somniferum, was first cultivated circa 3400 B.C. in lower Mesopotamia. Opium is an extract of the exudates derived from the seedpods of the flower. Ancient Sumerians, Assyrians, Babylonians, and Egyptians learned that smoking the extract would bring on pleasurable effects. The Sumerians referred to the poppy plant as Hul Gil or ‘joy plant’. Use of the plant later spread to Arabia, India, and China.

In the sixteenth century, Philippus von Hohenheim, better known as Paracelsus, invented laudanum by extracting opium into brandy. The alkaloids found in opium are significantly more soluble in alcohol than in water, so this new alcohol opium drink, essentially a tincture of morphine, easily drinkable and highly potent, became very popular. By the nineteenth century, vials of laudanum and raw opium were freely available at any English pharmacy or grocery store.

Progress continued in 1805 when morphine was first isolated from opium by the German pharmacist Wilhelm Sertürner. He called it morphium, after Morpheus, the Greek god of dreams. Morphine proved far more useful than opium for the medical field, as opium taken orally has unpleasant gastric side-effects. With the invention of the hypodermic syringe later in the century, pure morphine could be injected without these unpleasant side-effects. In Europe and America, morphine injection became very popular with high society and middle-class professionals. At the time, people believed that injecting morphine wasn’t addictive, and was a safe substitute for opium addiction, which when discontinued caused malaise, flu-like symptoms, and depression.

People soon realized that morphine was indeed addictive, and began looking for a non-addictive alternative. In 1874 the English pharmacist C.R. Alder Wright boiled morphine and acetic acid to produce diacetylmorphine. This new compound was soon synthesized by the German pharmaceutical company, Bayer, and put on the market in 1898 under the brand name Heroin.

Heroin was advertised as a “sedative for coughs” and became widely popular. Physicians handed out free samples. It was sold in dozens of countries, but doctors soon noticed that patients were consuming inordinately high quantities. Bayer halted production in 1913 and in 1914, the United States passed the Harrison Narcotic Act, a comprehensive set of opiate laws. In 1924, federal law was amended which made heroin use illegal for any reason, including medical. Within a decade, the Bureau of Narcotics had arrested over 50,000 users and 25,000 physicians for Heroin use.

Scientific Basics of Opioids

Pure opium contains sugars, proteins, fats, water, meconic acid, plant wax, latex, gums, ammonia, sulphuric and lactic acids, and numerous alkaloids, most notably morphine (10%-15%), codeine (1%-3%), noscapine (4%-8%), papaverine (1%-3%), and thebaine (1%-2%). Of these components, modern medicine uses morphine, codeine, and a number of derivatives of thebaine. It is thebaine from which the majority of today’s opioids are made. Thebaine has no analgesic effect itself, but can be used to synthesize hydrocodone (Vicodin), dihydromorphenone (Dilaudid), oxycodone (Percocet), and a number of other more obscure opioids. Completely synthetic morphine analogues include classes of drugs called the diphenylpropylamines (e.g. methadone), the 4-phenylpiperidines (e.g. meperidine), the morphinans (e.g. levorphanol) and 6,7-benzomorphans (e.g. metazocine). All contain a piperidine ring or part of its ring structure.

The entire pharmacologically active class of drugs inspired by the opium poppy are called ‘opioids’. This term includes compounds which occur naturally in the plant, such as codeine and morphine, semi-synthetics, which are compounds made from the combination of an opium product and another chemical, such as diacetylmorphine (made from morphine) and oxycodone (made from thebaine), and pure synthetics, compounds which are made with chemicals from other sources, such as methadone and fentanyl. The term ‘opiate’ refers only to natural and semi-synthetic compounds. Although ‘opiate’ and ‘opioid’ are often used interchangeably, use of the term ‘opiate’ is incorrect when referring to two very popular modern drugs, methadone, used in pain management and opioid maintenance therapy, and fentanyl, used in the Duragesic™ patch for long-term pain management. Additionally, the term ‘narcotic’, which originally meant, ‘agents which cause somnolence or induce sleep’, is today a legal rather than scientific term. Under the Single Convention on Narcotic Drugs Act of 1961 and the U.S. Controlled Substances Act (CSA), substances classified as narcotics include opioids, marijuana, and cocaine.

Opioids affect the body because their structure closely resembles a type of molecule called endorphins which are naturally produced by the body. Endorphins are small-chain peptides that activate our endogenous opioid receptors, a type of receptor site on specific neurons in the body. Endorphins are involved in controlling respiration, nausea, vomiting, pain modulation, hormonal regulation and itching. The analgesic effect of opioids is due to their influence on the way the brain receives messages of painful stimuli from the spinal cord. The patient in pain is still aware of the source of the pain, but it does not bother him anymore. Other physiological effects include the slowing of respiration and heartbeat, suppression of the cough reflex, and relaxation of the smooth muscles of the gastrointestinal tract. In fact, long before opioids were used as painkillers, opium was used to control diarrhea. They also cause miosis, or contraction of the pupils, a very reliable signal of opioid use. The release of histamine resulting from opioids can cause itching and perspiration, another telltale sign of use.

Owing to their resemblance to the body’s natural molecules, one of the most unique aspects of opioids is that their analgesic effect causes virtually no effect on the other sensory perceptions, consciousness, or motor function. All other substances with a painkilling effect, such as laughing gas, alcohol, ether and barbiturates also have, at their effective dose, an impairing effect on consciousness, motor coordination, intellect, and emotional control. “Individuals may take morphine or some other opiate for 20 years or more without showing intellectual or moral deterioration according to the common experience of physicians.”[1] The drowsiness which can be caused by opioids is generally experienced only at higher ‘recreational’ doses. Of course, while opioids do not impair consciousness, they can certainly have an effect on a user’s mental state.

The widely spread belief that morphine brings about an uncanny mental condition, accompanied by fantastic ideas, dreams, and what-not, is wrong, notwithstanding certain popular literature on the subject. The most striking thing about morphine, taken in ordinary doses by one who is not an addict, is that it dulls general sensibility, allays or suppresses pain or discomfort, physical or mental, whatever its origin, and that disagreeable sensations of any kind, including unpleasurable states of mind, are done away with. In fact, the suppression of pain is the only outstanding effect of morphine when given for that purpose.[2]

The emotional and mental effects of opioids are due to their action on the large cell complex known as the limbic system and nucleus accumbens. The lessening of painful and distressing stimuli can often induce a euphoric state in users. This state is described as having a profound sense of control and well-being, a warmth felt throughout the entire body, sometimes as a dreamy and relaxed state of contentment.

The initial effects were pleasant. Then, for a brief moment I noticed a feeling of unusual well-being; my bed was more pliable, the object in my room seemed more familiar, my body seemed lighter. It is true I noticed nothing extraordinary; I had no illusion or hallucinations. My breathing was easier and freer. I though about my personal affairs, my work and my dislikes. Things that had seemed difficult now seemed easy. Some of the problems of real life appeared to me in a new guise, with their solutions perfectly obvious.[3]

The Modern Use of Opioids

For historic and scientific reasons, there are a number of different opioids currently in clinical use. Morphine is considered by many to be the gold standard because it has been in use the longest. However in comparison to other opioids, morphine generally causes more nausea and pruritus[4]. All opioids are not the same, because the endogenous opioid system of the body is in fact quite complicated, with three main receptor type classifications known as mu, delta, and kappa, along with dozens of receptor subtypes which are still being identified. Because of the high degree of complexity of the body’s receptor systems and the variability of people’s metabolism, different opioids illicit different effects and have varied pharmacological profiles.

The use of opioids today is generally restricted to analgesic uses only, and even then, only for specific types of pain. Traditionally, opioids were restricted to situations where their use was only for a short duration, such as in post-operative pain, or elderly patients in late-term hospital care. Their use has liberalized somewhat in past decades to include other pain conditions, such as lower back pain, cancer, severe burns, migraine headaches, arthritis, myocardial ischemia, renal colic, and gout. Restrictions on opioid use are necessary in part because of the desire of people to abuse them for their mental effects, and in part because of the phenomenon of tolerance, dependence, and addiction.

While opioids may seem an ideal drug due to the absence of toxicity which accompanies so many modern drugs, they are not without their problems. Aside from the side effects which are due to the crude, non-receptor specific agonists used by modern science, the body begins to adapt to the presence of exogenous opioids by growing new opioid receptors. This causes a need to increase dosage to achieve the same effect. When the exogenous opioids are no longer administered, the body undergoes withdrawal symptoms due to the receptor adaptations. Symptoms of withdrawal can include restlessness, muscle and bone pain, insomnia, diarrhea, vomiting, cold flashes with goose bumps, yawning, tearing, nasal discharge, tremors, anxiety, and involuntary leg movements. These withdrawal symptoms are unpleasant for pain patients and recreational drug users alike, and can lead to drug seeking behavior, crime, and various social ills. While research continues to be done to eliminate the euphoric effect of opioids, prevent their abuse, refine their precision, and limit the onset of tolerance, the medical community of today is forced to work with opioids currently available, and does its best to work around their limitations.

About the Opioid Oxycodone

Oxycodone is a semi-synthetic opioid derived from the opium alkaloid thebaine. It is typically made into the salt form, oxycodone hydrochloride, a white, odorless crystalline powder that is highly soluble in water and slightly soluble in alcohol. It’s chemically known as 4, 5a-epoxy-14-hydroxy-3-methoxy-17– methylmorphinan-6-one hydrochloride. It has a high oral bioavailability relative to other opioids, between 60 and 87 percent, making it ideal for oral administration. Oral bioavailability is the percentage of active drug which reaches systemic circulation through oral administration relative to direct injection into the bloodstream. High oral bioavailability is desirable because it reduced the physical size of tablets, and gives the physician greater precision when titrating doses because of predictable pharmacokinetics. Oxycodone also has a high nasal bioavailability[5], between 50 and 65 percent, which makes it a good candidate for a nasally administered formulation, but also for nasal abuse. It can also be given intramuscularly, intravenously, subcutaneously, and rectally, although these routes of administration are less desirable and generally unnecessary.

The serum half-life following oral administration is 3.5 to 4 hours. Its effective duration of analgesic action is 3 to 4 hours. As with all pure opioid agonists, there is no ‘ceiling effect’ to the analgesia, so patients can continue to increase their dosages indefinitely as tolerance builds and maintain analgesic effect. Like other opioids, its most dangerous potential side effect is the respiratory depression by direct action on the brain stem respiratory centers. It depresses the cough reflex by action on the cough center in the medulla, can produce some degree of nausea and vomiting, causes miosis even in total darkness, and slows digestion of food in the small intestine. Headache, dry mouth, constipation, somnolence, pruritus, sweating, dizziness, and asthenia are also reported by a small percentage of users[6].

Abuse Liability

During a congressional hearing on August 28, 2001, Dr. Michael Levy, Director of Supportive Oncology and Director of the Pain Management Center at the Fox Chase Cancer Center, stated, “I could find no data in my review of the literature, or our clinical experience, that there was anything to say that oxycodone had any greater risk for addiction than morphine, hydromorphone, or fentanyl.” The label on certain oxycodone products states, “Roxicodone™ can produce drug dependence of the morphine type, and therefore, has the potential for being abused.”[7] Another states, “OxyContin™ is an opioid agonist and a Schedule II controlled substance with an abuse liability similar to morphine.”[8]

The reality is however a fair bit more complicated. When studying the addictive properties of a drug, there are many variables involved. Environmental setting and stimuli play a significant part, as does the route of administration. Generally speaking, the time to peak plasma concentration of a substance decreases as one moves from oral administration, to nasal, to intravenous injection, to smoking. This time to onset of effects is a critical factor in the addictive potential of a drug, as a substance which gives a quick and immediate high is more addictive to the brain than one which comes on gradually. For instance, cocaine can be smoked, injected, ‘snorted’, or taken orally. In its smokable ‘freebase’ form, referred to as ‘crack cocaine’, its habit forming potential is significantly higher than when it is taken nasally, generally in the powder form cocaine hydrochloride. Cocaine can also be taken orally, or the original leaf of the plant can be chewed, giving a much subtler, longer lasting and less addictive effect, though most modern users do not use these routes. With any given opioid, users who inject the substance become dependent and tolerant more quickly than those who use it orally.

There is also variability among the opioids themselves. When administered by the same route, opioids are metabolized by the body differently, causing different times to peak plasma concentration and different half-lives. The molecular structure also effects the times it takes for a substance to cross the blood-brain barrier. Diacetylmorphine (Heroin) reaches the brain in 15-30 seconds when injected, and when smoked, reaches the brain in around 7 seconds. Once in the brain, it is converted into morphine, but the ‘rush’ of its quick onset and volume of distribution make it inherently more addictive and give it a different subjective high compared to morphine. In terms of duration of plasma concentration, Methadone has a half-life of 15-30 hours, while hydromorphone has a half-life of 2-3 hours. This partially accounts for the reason methadone is used a maintenance agent, because is does not provide as intense a ‘high’, and only requires daily administration. However half-life alone is not the only predictor of abuse potential, because individual opioids effect different receptor subtypes and produce different subjective effects.

Subjective effects can vary from person to person, so while there are general trends in preference, one individual may have different preferences compared to another. When factoring in the variable of administration routes, the task of determining the exact abuse liability of a given opioid is then nearly impossible. Controlled clinical studies cannot attempt to replicate the real world setting of opioid users, nor consider price and availability. Manufacturers instead make reference to a substance ‘having an abuse liability similar to morphine’ in order to provide the most impact, because for historical and social reasons, perception is that morphine is a more dangerous or addictive drug compared to modern opioids. The truth is that certain opioids may indeed have higher inherent abuse liability than morphine. Based on the higher rates of side effects from morphine, and subjective user comments, it appears that oxycodone may indeed be somewhat more enjoyable for many, and therefore more addictive.

Subjective comments from users[9] [‘Oxy’ refers to OxyContin tablets whose active ingredient is oxycodone]:

“I’ve had some almost 99% pure Heroin and I have to say it’s definitely better than Oxy[10], especially when considering the high price of Oxy.”

“Heroin has a very ‘narcotic’ feel to it, but oxy has a seriously ‘medical’ feel to it. It’s a very ‘clean’ high.”

“When you intravenously inject Oxy, the rush doesn’t last very long at all. The major part of it is over in about 20 minutes. Heroin lasts a lot longer.”

“Oxy is over quicker. Much cleaner [compared to heroin] though. Not as sleep and not so much of the itch. Oxy doesn’t make me as nauseated. Oxy makes everything beautiful.”

“All I can say is that I get a very giddy happy high from oxycodone while I get a knockout loaded feeling from heroin.”

“Morphine Sulfate is useless to me orally. It is extremely not well absorbed by this route. Morphine is not quickly absorbed even by injection compared to some others, and tends to cause more histemic and emetic reactions, not to mention more respiratory depression. It has a nice dreamlike quality though. Not at the top, but still very nice to have.”

“You get a lot more ‘nod[11]’ with Heroin than with Oxy.”

“When you get that oxy buzz,” she says, “it’s a great feeling. You’re happy. Your body don’t hurt. Nothing can bring you down. It’s a high to where you don’t have to think about nothing. All your troubles go away. You just feel like everything is lifted off your shoulders.”[12]

The mental effects of oxycodone appear to be well liked by users, but distinctly different from heroin. Most intravenous users note that the oxycodone ‘high’ from injection is of a much shorter duration than from heroin. The effects of heroin generally seem to be more popular. On addiction and withdrawal:

“The addiction that comes with Oxy is nothing compared to the nightmare of being addicted to Heroin.”

“It takes a while to develop a significant habit with Oxy, but with Heroin, you can develop a large habit very quickly. Heroin seems to be much more addictive.”

“Oxy withdrawal is much more painful physically that Heroin withdrawal. The bone and muscle aches are much more severe than what occurs with Heroin withdrawal. However the anxiety involved with Heroin withdrawal is extremely intense. Much more so than with Oxy withdrawal.”

“I recently tried to stop taking them [OxyContin™ pills] for a day and I visited what I believed to be the bowels of hell! I got extremely nauseous, with heavy sweating, hot and cold flashes, uncontrollable coughing, diarrhea, insomnia, rapid heartbeat, watery eyes, excessive yawning, and depression - the worst feelings I've ever felt. It got so bad that I seriously contemplated ending it just so I wouldn't feel this way anymore.”

There does appear to be a high degree of consensus that heroin has a higher addiction potential. This may be due partially to the higher frequency of injection for heroin administration, though pharmacological factors are likely the main reason. Oxycodone users typically take the drug orally or nasally because extra purification steps are necessary to prepare it for injection [this applies to both aspirin and acetaminophen containing products as well as wax-matrix OxyContin, though the procedures are different]. The user comment about oxycodone withdrawal being more physically painful could indicate that it acts more effectively as a pain reliever, while the comment that heroin withdrawal causes greater anxiety may mean that heroin provides a more intense sense of relaxation and euphoria.

Oxycodone was originally synthesized in a German laboratory in 1916. It has been used in Europe by injection and orally since 1917. Oral 5mg oxycodone formulations have been available in the U.S. since the 1950's, typically combined with a co-analgesic agent such as aspirin or acetaminophen, which is referred to as a ‘‘combination analgesic product”. Common brand names have been Percodan, an aspirin formulation, and Percocet, Tylox, and Roxicet, acetaminophen formulations. In large doses, aspirin and acetaminophen can be toxic to the liver, stomach and kidneys. Therefore, drugs containing aspirin or acetaminophen are limited in their usefulness because a patient can only take up to a set amount per day to avoid toxicity. Because the pills were only available in 5mg formulations, patients who were using them for longer durations who began to develop tolerance were also forced to take high numbers of pills per day.

In the past decade, single-entity oxycodone products became available in the U.S., as 5mg immediate-release tablet formulations with common brand names Roxicodone, Percolone, and OxyIR. A liquid formulation named OxyFast also became available. According to the FDA, there are 59 oxycodone containing products currently available in the United States as of 2002. These single-entity oxycodone formulations removed the potential for aspirin or acetaminophen toxicity, but the problem of dosing frequency and pill numbers still remained because the effective duration of oxycodone is only 4 hours.

OxyContin™

OxyContin™ is the brand name of a 12 hour slow-release wax matrix formulation of oxycodone. It was developed by Purdue Pharma L.P. and approved by the FDA December 12, 1995 in 10mg, 20mg, and 40mg dosage forms. An 80mg dosage form was approved January 6, 1997, and a 160mg dosage form was approved March 15, 2000, though the company later suspended shipment of the product on May 11, 2001. The product label states, “OxyContin Tablets are a controlled-release oral formulation of oxycodone hydrochloride indicated for the management of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.” The unique traits of this product were that it was available in dosage strengths two, four, eight, and sixteen times greater that previous oxycodone formulations, and that the oxycodone was released slowly, providing a duration of effect between 9 and 12 hours.

Commercial sale and marketing of OxyContin began in January of 1996. At the time, competing products on the market for time-release high dose opioid formulations were 8, 12, and 24 hour oral formulations of morphine, and a 72 hour formulation of the opioid fentanyl in a skin patch. In part because of the aggressiveness of Purdue’s marketing campaign, and in part because of the unique and superior qualities of the drug, prescriptions for the drug increased dramatically, rising from approximately 300,00 in 1996, to 6,814,000[13] in 2001.

The current retail price for OxyContin tablets is $1.38 for 10mg tablets, $2.48 for 20mg tablets, $4.30 for 40mg tablets, and $8.16 for 80mg tablets. A generic 5mg capsule of oxycodone retails for 28¢[14], roughly half the cost of an equivalent OxyContin formulation. The majority of prescriptions filled are covered by some form of health insurance, so these numbers are not indicative of what the typical patient pays out of pocket, however OxyContin is clearly an expensive medication relative to its direct substitutes.

At issue is whether OxyContin provides superior pain relief compared to other oxycodone products and other time-release opioid formulations. There is no clear answer to this question, as medical professionals have differing opinions, and patient subjective feedback is not quantifiable.

There is no evidence that oxycodone offers any advantage over appropriate doses of other opioids, and it appears to have the same potential for addiction as morphine.[15]

“I am now a chronic pain patient who relies on OxyContin to be able to hold a job and be a productive member of society despite the constant pain I am in. I have tried many different pain medications, but only OxyContin has the prolonged pain control necessary for around the clock functioning. It does not make me high or drowsy and I am using the same dose I started on 6 months ago; there has been no need for an increase in dosage and I have no desire to take any more than I currently do.”[16]

There seems to be some degree of clinical consensus that oxycodone is superior to morphine in terms of side effects and other pharmacological parameters. Controlled-release oxycodone (CRO) has the characteristics of an 'ideal' opioid analgesic drug: short half-life, long duration of action, predictable pharmacokinetics, absence of clinically active metabolites, rapid onset of action, easy titration, no ceiling dose, minimal adverse effects, and minimal associated stigma. CRO has been shown to be effective in the control of pain caused by cancer, osteoarthritis, post-herpetic neuralgia, major surgery, and degenerative spine disease.[17]

It does appear that clinical studies have proven that oxycodone is a superior opioid to morphine in terms of incidence of nausea and hallucinations, and possibly more effective in certain types of pain control. More questionable, however, is whether there is any superiority of a controlled-release formulation of oxycodone over a regular formulation other than in terms of dosing frequency. One study seemed to confirm that controlled-release oxycodone provides additional benefits, however as is common with clinical studies in this field, the work was funded by the manufacturer Purdue Pharma, which causes some question as to its validity. Conclusions of scientific studies stated:

In comparison to other opioids, morphine generally causes more nausea and pruritus. It also has the disadvantage of being relatively hydrophilic, which delays its transport across the blood-brain barrier. In addition, morphine has several active metabolites whose levels can vary with renal or hepatic function. The drug apparently induces its own metabolism, which makes it difficult to maintain a steady serum level.[18]

…the two opioids [morphine and oxycodone] provided comparable analgesia. The total incidence of adverse experiences reported by the patients was similar, but significantly more vomiting occurred with morphine, whereas constipation was more common with oxycodone.[19]

There have been sporadic reports of agitation, sleeplessness, and dysphoria in patients taking high doses of oxycodone, which suggests that, in addition to µ-opioid effects, the drug also has kappa-opioid effects. It may thus have some added advantage for treatment of visceral pain, which appears to respond to kappa-receptor agonists.[20]

controlled-release oxycodone given every 12 hours was comparable with immediate-release oxycodone given four times daily in efficacy and safety....[21]

CR and IR oxycodone were equally effective in the management of cancer-related pain. The adverse event profiles of CR and IR oxycodone were similar.  Overall, however, significantly fewer adverse events were reported for CR oxycodone compared with IR oxycodone...[22]

OxyContin has certain other unique aspects relatives to available single-entity oxycodone formulations. The physical product is very small relative to its potency. An OxyContin tablet weighs approximately 3 times the milligrams of active content oxycodone. For comparison, the common brand name oxycodone combination analgesic product Percocet contains 5mg of oxycodone hydrochloride and 325mg acetaminophen, along with cellulose, starch, and other inactive ingredients, bringing the product weight to over 400mg.

The high concentration of active opioid product in OxyContin creates two major issues of concern. First is the possibly of a drug overdose, which can result if the wax-matrix slow-release mechanism is defeated, leading to an immediate release of the drug. Since its introduction, the product label for OxyContin has stated:

”OxyContin TABLETS ARE TO BE SWALLOWED WHOLE AND ARE NOT TO BE BROKEN, CHEWED, OR CRUSHED. TAKING BROKEN, CHEWED, OR CRUSHED OxyContin TABLETS LEADS TO RAPID RELEASE AND ABSORPTION OF A POTENTIALLY FATAL DOSE OF OXYCODONE.”[23]

So if one simply chews the tablet, breaking the wax-matrix, all of the oxycodone is released at once. For a 40mg tablet, that means instead of taking the equivalent of 2.6 Percocets every 4 hours, a user is consuming the equivalent of 8 Percocet tablets at one time. As the indicated dosage in non-opioid tolerant individuals is typically 1-2 Percocet tablets at a time, this is 4 times the recommended dose, and can in certain cases lead to fatal respiratory depression. In the typical adult, this dose would likely only lead to nausea and a period of immobility, however in susceptible individuals or when combined with another depressant drug, such as alcohol, the consequences can be more severe.

Of even greater interests to addicts and abusers is the possibility of nasal administration of the drug, which leads to an onset of peak effect in 25 minutes[24], compared to 60-90 minutes from oral administration (this includes if the tablet is chewed, which causes a greater peak but the same rate of onset). The outer coating of the OxyContin tablet is easily scraped off or wiped off with a wet paper towel, and with moderate force the wax-matrix core can be crushed into a fine power. This powder has active oxycodone concentrated at approximately 300mg/g, compared to the roughly 12 mg/g resulting from a crushed Percocet tablet, a 25 fold greater concentration. When a user attempts to snort a Percocet tablet, the mucous membrane becomes saturated with powder, causing sub-optimal absorption of the drug, while with OxyContin powder, the mucous membrane allows complete absorption. Coupled with oxycodone’s approximately 60 percent[25] nasal bioavailability, relatively high compared to other opioids, such as morphine at approximately 10 percent[26], the phenomenon of nasal abuse of OxyContin has become popular.

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The Media

According the LexisNexis academic search engine there were 573 stories in major U.S. papers between March 11, 2000, and March 31, 2003 which mentioned OxyContin in their title or lead paragraph. Yet despite the fact that the drug was introduced in January of 1996, there were no mentions of it in the four years and two months before The Columbus Dispatch, a local newspaper in Ohio, ran a story on March 11 about a doctor named John F. Lilly who had been arrested for illegally prescribing prescription drugs, including the drug OxyContin.

The story, written by staff reporter Bob Dreitlzer, said that Dr. John Lilly had been arrested as he tried to buy an automatic weapon from an undercover police officer. When searching his home, authorities found six automatic weapons and $400,000 cash. The arrest had followed an investigation in which authorities said Dr. Lilly had been illegally prescribing the drugs Valium, Vicodin, and OxyContin, among others. The article stated that, “[OxyContin] is a drug related to morphine that comes in a time-release capsule.” It also quoted a local prosecutor who said, “"For whatever reason, [OxyContin] is the drug of choice among users on the street here.'' The article headline ran, “Officials Hope Doctor's Arrest Will Stem Flow of Illegal Drugs Scioto County Man Charged.”[27]

Two months later on May 21, The Boston Globe ran a story on page 22 of section D titled, “A Prescription for Crime: Abuse of 2 Painkillers Blamed for Rise in Violence in Maine's Poorest County.”[28] The article began with a comment from the Washington County sheriff saying his 40-bed jail had been filled to capacity since December with people caught during break-ins and armed robberies while in pursuit of “heroin-like narcotics”. The story stated that drug agency statistics show that the remote county's per-capita use of OxyContin was more than twice the state average. It also mentioned that the previous year, “…the Maine Drug Enforcement Agency nearly doubled its arrests for pharmaceutical narcotics.”

A month later on June 27, the Times-Picayune, a New Orleans newspaper, ran the headline on its front page, “Potent New Painkiller on the Street, Cops Say; Task Force Investigating Street Sales of 'New Vicodin'.”[29] The first line stated, “A potent and addictive painkiller called Oxycontin may soon replace Vicodin as the most heavily abused prescription drug, according to federal and local authorities.” A local representative from the Drug Enforcement Administration was quoted as saying, “We're just starting to see Oxycontin abused and have started active investigations.”

However the major newspapers had yet to pick up on the OxyContin story. Small local papers in Maine and Kentucky began running stories with increasing frequency, but during the next six months, there were only 3 back-page stories in national newspapers which mentioned OxyContin, usually in reference to drugstore robberies. Finally, on February 8, 2001[30], The New York Times picked up on an announcement made the previous day that state and federal authorities in Kentucky had arrested 201 accused drug dealers for distributing the prescription drug OxyContin in a series of coordinated raids dubbed ‘Operation OxyFest’. The local U.S. attorney Joseph Famularo was quoted as saying that at least 59 people had died from OxyContin overdoses in eastern Kentucky during the prior year.

The New York Times ran the Associated Press feed on page 20, but the next day, February 9, ran their own story on the front page. The headline read, “Cancer Painkillers Pose New Abuse Threat.”[31] That night, the ABC television show 20/20 had an episode called “Painkiller ‘Epidemic’” based on the Kentucky drug raids. Following suit, The Washington Post ran, “Virginia Police Fear Rise of New Drug,”[32] on the front page of its metro section the next morning.

The major national newspapers had in fact been beaten to the punch by Time Magazine, which had run a story titled, “The Potent Perils of a Miracle Drug,”[33] on January 8. The line, “OxyContin is a leading treatment for chronic pain, but officials fear it may succeed crack cocaine on the street,” was run below the title. U.S. News & World Report featured an article titled, “The ‘Poor Man’s Heroin’,”[34] on February 3, based on the arrest of Dr. Lilly in Ohio from the previous March. After a two month pause, on April 9, Newsweek’s cover read “Painkillers”, and inside had the story titled, “How One Town Got Hooked,”[35] about the rampant abuse of ‘oxy’, as it was popularly referred to, in the rural town of Hazard, Kentucky. Another story in the same issue was titled, “Playing with Pain Killers.”[36]

There seemed to be common themes in the stories and to the media’s behavior. They generally portrayed OxyContin as a uniquely addictive, ultra-powerful narcotic with a ‘heroin-like’ high. They also suggested that the death toll from this drug was rising rapidly and eclipsing the deaths from abuse of other prescription drugs. Lastly, they gave little attention to the patients who were being helped by the drug, instead searching for the most sensational sound bites available. John Burke, Command of the Warren County Ohio Drug Task Force had this to say:

Most of my peers that I spoke to, and myself, were frustrated with the media when we were interviewed. They were anxious to hear stories of OxyContin® abuse, but were largely disinterested in comments that the drug had a very legitimate function with the vast majority of its users.

I recently invited a local television station to spotlight a pharmaceutical diversion investigator that I hired to address the overall problem of prescription drug abuse in our county. They photographed him meeting pharmacists in our county and allowed him a brief statement about drug diversion. They had asked about OxyContin®, and I told them I did not know how much of a problem the drug was in our area until I got feedback from my new investigator; until he had some time to gain experience in our area.

The story aired two nights later and I knew there was a problem when I saw the promotional piece. The story strongly insinuated that I hired the investigator because of the OxyContin abuse issue! This, of course, was totally untrue, but rebuttal opportunities are few and far between.[37]

At the time the stories were run, a thorough examination of the toxicological data of the supposed OxyContin deaths had not been done, so the press chose use the number given by the local U.S. attorney, or whoever was willing to provide them with a number. According to the February 9^th New York Times story, U.S. attorney for the east district of Kentucky Joseph Famularo had stated, “I personally counted 59 deaths since January of last year that local police attributed to addicts using the drug, and I suspect that's pretty conservative.”[38] In addition, without any hard numbers as to the extent of the abuse or information about the exact nature of OxyContin’s addiction potential, they began comparing it to crack cocaine and heroin.

The Associated Press quoted Harlan County Kentucky sheriff's department detective Roger Hall, as saying, “They'll [an OxyContin abuser] kick a bag of cocaine out of the way to get to 'Oxy',”[39] for their story about Operation OxyFest. The Port St. Lucie News in Florida ran with “The New Crack” in its headline. U.S. News & World Report gets credit for popularizing the phrase ‘poor man’s heroin’ with their February 3 article title. Though if they had done any hard research, they would have realized that the street price of OxyContin was greater than that of Heroin nearly as soon as it reached the black market. Perhaps the term was meant to refer to the fact that OxyContin was first popular in rural ar