Heroin Epidemic. The United States is experiencing an epidemic of heroin addiction and a sharp rise in opiate over-dose death.  Contrary to addicts being introduced to opiate addiction through street heroin, 75% of new addicts became addicted through prescription opiates (Cierco et al., 2014).  Deaths from prescription opiates exceed death from heroin (Volkow et al., 2014).  The surge in heroin addiction is explained by the ubiquity of prescriptions for pain medications.  When the prescription opiate OxyContin becomes too expensive ($80/pill), people switch to the cheaper street heroin ($5-10/hit).  In 1999, there were on average 10 opiate deaths per day.  By 2012, there was one death every half hour (Quinones, 2015 ).

How OxyContin Came to Be a Big Seller?   Back in the 1950s, physicians were very reluctant to prescribe opiates for cancer patients who were dying.  A shift in this attitude came with several publications.  A letter to the New England Journal of Medicine by Jink and Porter in 1980 reported on a review of the hospital records of patients treated with opiates finding that less than 1% became addicted.  (In fact, this letter to the editor did not specify the conditions for which patients received opiates while in the hospital nor the dosage or duration of exposure to opiates).  This was followed by a publication in the journal Pain in 1986, by Portenoy and Foley regarding low rates of addiction in 38 patients treated with opiates for diverse conditions about a quarter of whom experienced back pain.  The 38 patients were not evaluated for whether they exhibited withdrawal symptoms post discontinuation of opioid.  However, only two patients posed management problems for doctor because they requested escalation of their dosages.  In the decades to follow, these two publications were cited as the evidence for low addictive liability of the opiates in persons experiencing pain.  Pain clinics were opened throughout the country.  Jink & Porter and   Portenoy &Foley were widely cited despite the fact that these two publications were not relevant to the question of whether patients with diverse pain conditions were invulnerable to opiate addiction, defined as experiencing drug withdrawal after opiate discontinuation.  In 1989, D. E. Weismann and J. David Haddox et al. published an article in Pain suggesting that if a pain patient asks for higher levels of medication, a sign of “pseudo addiction”, this was an indication that pain was not adequately treated and that dosage should be increased.  (J. David Haddox later went to work for Purdue Pharma, the maker of OxyContin.)   (See Quinones, 2014, for full account.)

The train had left the station.  In 1996, James Campbell, president of the American Pain Society, in a speech characterized pain as the fifth vital sign.  The American Pain Society employed the slogan “Pain: the Fifth Vital Sign.”  In 1998, the VA made it mandatory for pain to be assessed right along with pulse and blood pressure.  The Joint Commission for the Accreditation of Healthcare Organizations, which certifies all major hospitals, made compliance with evaluating pain a criterion for accreditation (Quinones, 2014).

The Marketers Take Over for Promotion of Pharmaceuticals.  Quinones characterizes Arthur Sackler, a physician who directed the Creedmoor Institute of psychiatry in New York in the 1950s, as playing a big role in medicine becoming a consumer product.  Sackler opened an advertising firm for pharmaceutical companies, William Douglas McAdams.  Sackler and his brothers established medical journals which were effectively advertising devices for pharmaceutical houses.  In the 1960s, Sackler was influential in marketing efforts for valium.  Sackler recommended the direct marketing to physicians with drug reps visiting individual physician offices.  This became the model for Purdue Pharmacy, the makers of OxyContin.

In 1995, the FDA approved Purdue Pharmacy’s claim that OxyContin, because of its extended duration release, had lower addictive potential.  Curtis Wright headed the FDA committee approving this claim, although he did add notes of caution.  (Curtis Wright later went to work for Purdue.)  William Douglas McAdams, the firm founded by Sackler, became the advertising firm for Purdue.  Purdue Pharma sponsored physician CME events all over the country.  They all cited the landmark Porter and Jink’s work as evidence supporting the low vulnerability of patients with pain to opiate addiction.  They all referred to the low risk of addiction with extended release OxyContin.  Sales reps offered OxyContin coupons to physicians who distributed them to patients.  OxyContin coupons could be exchanged at pharmacies for an initial free OxyContin prescription.  This initiated the opiate epidemic associated with the wide-spread prescriptions for OxyContin (Quinones, 2014).

In recent times, more notes of caution have appeared in the literature.  In 2007, Purdue Pharmacy pled guilty to misbranding OxyContin (Quinones, 2014, 75%; Meier, 2007). Portenoy characterized his promotion of the idea that opiates would not be addictive for those in pain as misguided on the website Physician’s for Responsible Opiate Prescribing (see the five minute video, Addiction is NOT rare in pain patients).

US Government’s Response to Heroin Epidemic. Nora Volkow of NIDA, Tom Frieden of the CDC, and Michael Botticelli of the White House’s Office of Drug Control Policy have advocated the expansion of methadone programs and buprenorphine treatment to respond to the epidemic.  SAMSHA, the federal agency which regulates methadone maintenance programs, suggests that we call these interventions “Medication Assisted Treatment” (MAT) rather than opiate substitution programs so as not to stigmatize persons.

SAMSHA’s New Rules.  Methadone programs have been around since the mid-1950s in New York State.  Under the Narcotic Treatment Act of 1974, methadone maintenance clinics became legal in the United States, although states vary in state regulations.  What is new is that SAMSHA has effectively rewritten the rules on how methadone maintenance clinics are run.  Whereas the law of 1974 limited methadone to those who had been addicted for a year, the SAMSHA (2012, Tip 43) guidelines allow for those who are not physically dependent on opiates to receive methadone.  While initially the goal was to wean patients off, SAMSHA (2012) advises directors of clinics that when a patient requests a dosage reduction that they should “educate” the patients on the importance of staying on their Medication Assisted Treatment.  There is no duration limit on MAT.  Moreover, there is no longer a limit on dosage.  Given that stress is a reliable precipitant to relapse in drug abusers, SAMSHA discusses increasing dosage during stressful times (see page 77, in SAMSHA’s Tip 43, Medication-Assisted Treatment).

Buprenoprhine is a partial agonist?  The newcomer on the scene for treatment of opiate addiction is buprenorphine.  The drug company characterizes buprenorphine as a “partial agonist” at a mu-receptor and an antagonist at a kappa receptor.  In the body, there are 3 types of receptors for opiates: mu receptors, kappa receptors, and delta receptors.  Mu receptors produce the pleasurable effects and the compulsion to use opiates.  Kappa receptors counter the mu-effects.  Upon hearing that buprenorphine is a partial agonist, I wondered “how?”  I’m always amazed at the amount of information available to biologists.  For almost all receptors, someone knows the shape of the receptor, the amino acids in the receptor that a ligand (neurotransmitter or drug) interacts with, the proteins in the body of the neuron that are influenced when the ligand binds, and the downstream effects on the ligand/receptor binding.  So what is making buprenorphine different from methadone, morphine, and OxyContin?  It did not take long to find out.

Turns out that buprenorphine not only interacts with the mu-receptor but also another protein called a “Regulator of G-protein Signaling” which turns off activity at the mu-receptor.  The problem is that tissues and brain areas vary in terms of whether the neuron contains the “Regulator of G-protein Signaling”.  As such, buprenorphine will only demonstrate this effect on some outcome measures but not on others.  Thus it will be a “partial agonist” on some measures but not on others. The case has been made that buprenorphine is less likely to produce an overdose via respiratory depression than other opiates.  However, all bets are off if buprenorphine is used with another drug.  Many people on buprenorphine die when they combine “bup” with alcohol.

Opiate Agonists Are Very Dangerous Drugs: Lack of Guidelines on Safe Dosing.  Deaths of opiate patients being treated in pain clinics began to escalate around 1999.  This correlated with a switch from low potency to high potency opiate prescribing according to a study by Franklin, Mai et al. (2005) in American Journal of Industrial Medicine (Quinones, 2015, 58%).  Mai and Franklin had noted these trends in the statistics for those persons receiving Workman’s Compensation.  Mai contacted to Jennifer Sabel, an epidemiologists, to ascertain whether their findings reflected a more general phenomenon. According to Quinones (2015, 66%), Sabel queried pain specialists regarding a maximum safe dosage.  Purdue Pharma responded with outrage suggesting that limiting dosing represented prejudice and ignorance.  The absence of a ceiling dose was noted in the pain field.  Interestingly, at the present time, SAMSHA has no maximum dose limit for methadone and buprenorphine for those physicians in MAT clinics.

A problem with establishing safe dosing is the opponent process phenomenon.  Psychologists have recognized that for any process imposed on the body, the body will respond in the opposite direction, i.e., with an opponent process.   The opponent process is triggered by environmental cues.  For example, if a person exercises in the same gym, the environmental cues at the gym will trigger an opponent process so that the workout feels less exhausting.  However, if the person exercises in a new environment, where the opponent process has not been conditioned, then the same workout will feel much more exhausting.  The same phenomenon is relevant to opiate drugs.  A safe dose in the customary environment may not be safe in a new environment.

Increased Risk When Opiates Are Combined with Other Drugs.  Methadone and buprenorphine compete for the same enzymes as many antibiotics, antidepressants, and antipsychotics for their metabolism (removal from the body). As such the effective dose of methadone is much higher than when people are not on these other medications.  In addition, methadone can result in cardiac arrhythmias because of a change in electrical conduction in the heart (QTc prolongation), although buprenorphine is supposed to be a little safer on this outcome.  However, many antidepressants and antipsychotics can also increase QTc prolongation.  With regard to danger associated with cardiac arrhythmias, the probability of an adverse event increments with each additional drug.  Studies of opiate overdoses find that antidepressants, benzodiazepines, and antipsychotic drugs are associated with lethal overdoses.  The SAMSHA guidelines recommend screening for co-occurring disorders.  The Tip 43 guidelines do mention those medications which compete for the same enzymes as methadone but don’t discuss risks associated with multiple medications that increase risk of cardiac arrhythmias.  The drug interactions increase the lethality of opiate drugs.

Dilemma of Other Addictive Drugs in Methadone Maintenance.   It has been known for a long time that most heroin addicts do not limit their drug consumption to heroin.  When people are in methadone maintenance, they often don’t quit using cocaine, marijuana, or alcohol.  (In terms of drug interactions, there is some suggestion in the literature that concurrent use of marijuana actually decreases the opiate dosage required to curtail cravings.)  While SAMSHA does suggest that Opiate Treatment Programs screen for other drugs, SAMSHA is unclear about what should happen if the urine tests positive.  (According to SAMSHA instructions, we are to use the language ‘tests positive’ rather than ‘dirty urines.’)  SAMSHA is clear that patients should not be dis-enrolled from the program.  Sanctions can include limiting take-home dosages of methadone.  They also suggest switching the patient to long-acting naloxone.

Naloxone, seriously?  When I read the suggestion to switch to Naloxone, I was really confused.  SAMSHA seems to want to avoid an addict’s use of street heroin at all costs.  Naloxone will displace all opiates (buprenorphine, heroin, morphine, methadone) from the mu-receptor but won’t induce any signaling in the neuron.  In fact, naloxone will displace natural opiates (endorphins) from the receptor as well such that even any placebo effect on pain suppression is lost.  In terms of listed side effects, naloxone causes lethargy, anxiety, a decrease in pain tolerance, joint and muscle pain, and induces immediate withdrawal signs if taken by someone who is dependent on opiates.  There’s a history of poor compliance among addicts with naloxone.  SAMSHA knows this.  Why would they introduce a drug option that could undermine all their efforts to set up a self-sustaining high compliance program?

To be fair here, long-acting naloxone does decrease relapses in alcoholics who are trying to maintain sobriety.  So we can call it “evidence-based treatment”.  Drug addicts are not going to crave their drug(s) of choice when taking naloxone.  The problem is that with naloxone patients aren’t going to want anything else either, such as food, going to work, etc.  (Yes, naloxone has been considered as a potential treatment for obesity.)  Of course the drug companies don’t include measures such as lethargy and apathy when they are doing the drug trials, but the impact is clear in the animal literature.

The Staff in Methadone Maintenance Clinics.  So we’re back to the real problem of what to do about methadone and “bup” patients that use other drugs.  Especially when used in combination with alcohol, methadone and buprenorphine can induce overdose.  Another complicating factor with the SAMSHA’s goal of increasing the numbers on MAT is the paucity of knowledgeable clinicians who approve of MAT in America.  About 45% of the non-physician clinicians in substance abuse treatment in this country are persons in recovery.  They generally are strong adherents to Twelve Step Principles.  The goal for Twelve Steppers is freedom from all mood and mind altering drugs.  They don’t generally approve of MAT.  Historically, physicians in Addiction Medicine often are recovering people as well.  So where are all these substance abuse professionals to staff methadone maintenance clinics going to come from?  The danger in by-passing the current work force and developing a new work-force is that it will take some time for the new recruits to develop expertise in detecting when a client is abusing alcohol and knowing the population.

Ironically, while the government’s response to the opiate epidemic is to increase MAT with more liberal dosing practices, they are also more closely monitoring pain clinic doctors.  At a recent International Opioid Conference I attended in Boston, most of the presenters were doctors working in hospice or pain clinics.  The lawyers talked about pain-management doctors being entrapped by clients working for the DEA and then facing criminal charges and fines.  (The director of prestigious Stanford pain-management clinic was recently visited by the DEA.)  At the conference, the director of the Stanford clinic talked about his clinic’s response to the DEA scrutiny.  They have developed very rigorous screening batteries to detect those pain clinic patients most likely to become addicts; they have developed elaborate informed consent procedures entailing a 20 minute video presentation for all prospective patients; they implemented drug screening procedures with point of care methods followed by laboratory screening involving very expensive assays.  The bottom line is that costs have increased dramatically, further contributing to the cost of medical care, which presently is already the most expensive system in the world.  This all seemed ironic to me, because if given a pain patient is indeed an addict, then the protocol is to refer to methadone or buprenorphine.  Once the patient becomes a methadone or buprenorphine patient, doctors are to “educate” the patient about the dangers of ever trying to become abstinent.  Moreover, the rationale for methadone is that the dosage is to be sufficiently high so that tolerance develops such that heroin, at any dose, will fail to produce an effect (opiate blockade).

We’re Off to Another Epidemic?  Given that buprenorphine is now in a clinical trial to treat medication resistant depression, we’re probably going to have a lot of people taking opiates.  Then we’ll have many dilemmas over what to do if the patient escalates the “bup” dose without permission or uses an unapproved medication.  Physician may wonder whether they need parole officer training. But, whatever the outcome for the patient, more money will be spent on drugs, monitoring, and auxiliary personnel.  With more opiate drugs circulating in the general population there will probably continue to be many opiate related deaths.   Thus, the U.S. is embarking on another big experiment with the drug companies and another big increase in the cost of medical care in this country.

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