An Article by Mike Berens and Ken Armstrong, Seattle Times, discusses some of the problems with using methadone as a first-line treatment for pain:

When it comes to battling pain, Washington health officials have encouraged doctors to reach for methadone, a powerful and inexpensive prescription drug. For the past decade, the state has declared methadone to be as safe and effective as any other narcotic painkiller.

Methadone

But in a striking reversal that has gained momentum this week, doctors are receiving stark warnings that methadone is riskier and more dangerous — a drug of last resort — because it’s unpredictable and poses a heightened risk of accidental death.

“It’s a dangerous drug because it accumulates in the body and people die in their sleep,” Dr. Jane Ballantyne, a pain specialist at the University of Washington, said Friday. “It’s very tricky and difficult to use safely.”

Ballantyne and the university are helping spearhead a series of state-sponsored training programs to educate physicians, pharmacists and advanced nurse practitioners about the risks of pain drugs.

Earlier this week, while delivering a continuing medical education course for dozens of physicians and other medical professionals at the university, Ballantyne presented a slideshow in which she cautioned that methadone “should be considered a last option opioid, never a first line opioid.”

The state’s effort is a response to a Seattle Times series, “Methadone and the Politics of Pain.” The investigation, published in December, detailed that at least 2,173 people in Washington have died from accidental overdoses of the drug since 2003.

The Times found that year after year, a committee of state-appointed medical experts sanctioned methadone, empowering the state to designate it a “preferred drug” and steer people with state-subsidized health care — most notably, Medicaid patients — to the drug in order to save money.

The state has included only two drugs, methadone and morphine, on its preferred list of long-acting pain drugs.

During the committee’s meetings, officials from state agencies that have a financial stake in methadone’s selection consistently deflected concerns about the drug.

Methadone’s death toll has hit the hardest among low-income patients. Medicaid recipients account for about 8 percent of Washington’s adult population but 48 percent of methadone fatalities.

After the series, the state sent out an emergency public-health advisory that singled out the unique risks of methadone.

Medicaid officials faxed a health advisory to more than 1,000 pharmacists and drugstores about methadone, as well as about oxycodone, fentanyl and morphine. The state Department of Health mailed advisories to about 17,000 licensed health-care professionals.

The health advisory confirmed that Washington ranks among states with the highest rates of opioid-related deaths, exceeding the number of deaths each year involving motor vehicles.

Most painkillers, such as oxycodone, dissipate from the body within hours. Methadone can linger for days, pool into a toxic reservoir and depress breathing. With little warning, patients fall asleep and don’t wake up. Doctors call it the silent death.

Ballantyne noted that methadone is an indispensable drug and plays an important role in the treatment of many patients. However, due to the heightened risks, methadone should be prescribed only by those with extensive training and experience — and only after every other option has been exhausted.

Dr. Jeff Thompson, chief medical officer of the state’s Medicaid program, now readily agrees that methadone use carries unique risks and that it should not be the first choice if other drugs are equally suitable.

He said physicians are stepping up efforts to unravel the long-term impact on the body from prolonged use of prescription drugs now that Washington’s new pain-management law has gone into full force beginning this month.

The groundbreaking law requires practitioners to follow new standards for treatment and record-keeping. It also requires prescribers to consult with state-certified pain experts when narcotic dosages reach higher thresholds.

While the law’s goal is to lower doses and, if possible, wean patients from narcotic pain drugs, doctors are finding the task more difficult than hoped, Thompson said.

For instance, methadone patients can suffer prolonged withdrawal symptoms, like nausea and depression. With most pain drugs, withdrawal subsides within a week. Methadone’s grip can last for months, even years, he said.

State officials will review methadone’s role on the state’s preferred drug list during a meeting next month.

“I think we’re going back and relearning how to treat pain,” Thompson said.

As I give my last post more thought….  I wonder if there is ANY clinical difference between $uboxone at $7 per dose, vs. generic buprenorphine at $2.33 per dose?  Researchers out there– can anyone send me a reference?

Read my last post for details– but the essence is that naloxone is destroyed when Suboxone is taken properly (orally, sublingually), and has no action whatsoever– on that issue there is scientifc agreement (although there is a great deal of ignorance among prescribers about this fact).  The ONLY think naloxone does, is to supposedly serve as a deterrent to IV injection of buprenorphine.

Sounds good, but…  we know that people divert Suboxone intravenously, naloxone and all.  Buprenorphine binds opioid receptors very tightly- so tightly that the naloxone doesn’t effectively compete with buprenorphine.

The State of WI requires Medicaid patients to take expensive Suboxone Film, whereas in other cases they require prescribing the generic.  What is the argument for requiring the film?  RB would argue (now that the tablet has lost the luster of being on-patent) that the film is harder to ‘divert’– i.e. to inject.  But frankly, the intravenous diversion of buprenorphine is a tiny issue compared to things like heroin addiction and a budget crisis.  Most of the diversion of buprenorphine, either Suboxone or generic, is not injected, but rather taken orally to ward off withdrawal– and the film makes no difference in that case.

Insurers, likewise, are wasting millions of dollars (literally) by paying for Suboxone— sometimes exclusively(!)  Have the bean counters fallen asleep on this issue?

I have nothing personal against Reckitt-Benckiser, beyond the fact that they refuse to engage in conversation with me.  If the good Brits at RB have discovered a way to suck millions of dollars from the weakest members of society, more power to them.  But I am a big fan of intellectual honesty, particularly in regard to the science behind medical practice.  So if someone has evidence that $uboxone is clinically different than generic buprenorphine, whether used properly or injected, please send it my way.

This post is from a couple years ago;  I think it is important for people to have a basic understanding of how buprenorphine removes opioid cravings, so I’m republishing the post.

Note that naloxone has NOTHING to do with the effects of Suboxone.

In this video I explain why the ceiling effect is so important to the effects of buprenorphine for treating opiate dependence.

I have shared my thoughts about ‘Suboxone Film,’ a product that serves only one purpose:  to block generic competition from entering the Suboxone market.  Below I’ve copied a Bloomberg article that discusses the current nature of the buprenorphine/naloxone business, and the efforts by RB to prevent market penetration by generics– something that would lead to price reductions for healthcare consumers.

Unfortunately, the Bloomberg article overlooks the most significant threat to the profits of Reckitt-Benckiser.  This threat is mitigated only by the ignorance of many of the physicians who prescribe Suboxone.  The threat to profits consists of a simple fact that RB does not want anyone to realize:  that the generic equivalent of Suboxone is already available, in the form of orally-dissolving tablets of buprenorphine.

I encourage physicians who doubt my comments to do their own ‘due diligence’ and break out their old pharmacology textbooks.  I have a hard time understanding how people who graduated from accredited medical schools can get things as wrong as they do with this issue.  I sometimes present opinions, but not with this post.  The facts about buprenorphine and naloxone that I’m about to describe are described in any pharmacology textbook— e.g. Goodman and Gilman—and are not in dispute in any way.

Suboxone consists of buprenorphine plus naloxone.  Naloxone is an opioid antagonist that is added to reduce diversion of Suboxone in the form of intravenous injection of a dissolved tablet.  Naloxone is NOT ACTIVE when not injected.  The molecule is poorly absorbed through the oral mucosa because of the molecule’s size and poor lipid-solubility.  Instead, naloxone is swallowed, absorbed from the small intestine, and totally destroyed at the liver before reaching the systemic circulation through a process called ‘first pass metabolism.’

I suspect that some physicians confuse naloxone with the similarly-named substance naltrexone, an opioid antagonist (blocker) that IS orally active. There is NO naltrexone in Suboxone.

All of the beneficial aspects of Suboxone come from the partial agonist buprenorphine.  The ceiling effect of buprenorphine causes a reduction in cravings through a process that I’ve described in earlier posts.  Naloxone, on the other hand, does absolutely nothing to reduce cravings, to increase safety, to reduce euphoria, etc, provided that the medication is not injected.

The confusion surrounding buprenorphine essentially consists of intellectual laziness or intellectual dishonesty by the physicians who prescribe the medication and the pharmacists who dispense it.  I realize that not all doctors are cut out to be ‘physician scientists’ who understand pharmacology in great detail.  But I am particularly disappointed that the large organizations that supposedly oversee the science of addiction treatment have dropped the ball on this issue. I don’t know why groups like ASAM and SAMHSA don’t get it– whether the problem is ignorance, or whether there are mutually beneficial relationships between these organizations and RB that encourage the organizations to foster ignorance among
patients and doctors.  I don’t belong to the organizations primarily for this reason– and I blame ASAM and SAMHSA for the current status of addiction treatment as the ‘no science zone’ of modern medicine.

 A few examples of intellectual laziness: 

Example 1:  Physicians who prescribe Suboxone often say that one shouldn’t use buprenorphine ‘because it doesn’t have the opioid blocker and therefore….’ (add whatever here– it causes euphoria, it is addictive, it isn’t safe– any or all of these comments). The statement is partially correct. Generic buprenorphine does not have the opioid blocker naloxone— but naloxone is irrelevant to the actions of Suboxone!

There are TWO opioid blockers in Suboxone, but only one is clinically relevant—the one that is in both Suboxone and generic buprenorphine.  What is the relevant ‘opioid blocker’ that IS
in both Suboxone and generic buprenorphine?  Buprenorphine!   As a partial agonist, buprenorphine has antagonist properties that are responsible for ALL of the effective clinical properties of Suboxone.

Example 2:  Refusing to consider the cost of medication as a factor that determines access to treatment.  Some docs make ‘fear of diversion’ the only factor in determining what to prescribe.  Discussions with hundreds of opioid addicts over the years have convinced me that buprenorphine is rarely a drug of choice.  Rather, it is used by addicts who are sick and tired and want a break from using without withdrawal, or by addicts who have no money or access to agonists.  In such cases, buprenorphine or Suboxone are equally effective– and equally diverted.  When I ask addicts new to treatment about their injecting habits, I often ask whether they injected buprenorphine or Suboxone.  The typical response is either ‘can you do that?’ or ‘why would I do that, since heroin is cheaper?’

In my area, an 8 mg tab of buprenorphine costs as low as $2.33.  This low cost should be part of the equation for choice of medication, just as it is for other illnesses.  Does anyone doubt that there are some people kept from treatment by a price differential of 300%?!  Is it ethical to fear diversion so greatly that treatment is effectively withheld– for a condition with the fatality rate of opioid dependence?!   I’m sure readers know my answer, especially when there are effective ways to reduce diversion, such as close monitoring of prescribed doses, a ‘no replacement’ policy, and drug testing, among others.

Example 3:  There is some question whether the naloxone in Suboxone does anything to reduce diversion. Buprenorphine patients on my forum  who have injected Suboxone in the past have claimed that they did not experience withdrawal from either Suboxone or buprenorphine, consistent with what I would expect from combining a low-affinity antagonist with a high-affinity partial agonist.

Note: Injecting ANYTHING is in essence taking your life in your hands, and I strongly encourage anyone in such a position to seek treatment immediately.   Really—don’t do it.

Example 4:  Insurers generally refuse to cover generic buprenorphine (the generic form of the RB drug Subutex), even though it is much cheaper than Suboxone.  The one time they WILL cover Subutex or buprenorphine is for women who are pregnant or nursing.  The argument is that we shouldn’t expose the fetus/infant to one more drug (naloxone), since that drug isn’t necessary to the actions of Suboxone.  I agree with the argument, and wonder why it is extended only to the fetus?  Why does mom or dad have to be exposed to an extra substance(naloxone) that isn’t necessary to the actions of Suboxone?

I struggle to understand the insurance issue, as I would expect that someone at some major insurer would know enough about pharmacology to save money on Suboxone by favoring generic buprenorphine.

The ultimate of silliness is that the State of Wisconsin requires that people on Medicaid use only Suboxone FILM.  Getting Abilify for a patient is virtually impossible without first using a variety of older, cheaper medications… but the squishy arguments in favor of Suboxone Film push the med up the formulary chain past an alternative that sells at a fraction of the cost.  The film/Medicaid situation is doubly dubious, as we have the arguments for buprenorphine over Suboxone, and the even less-sound argument for Suboxone Film being favored over the tablet.

RB apparently convinced the state that for Medicaid patients, only the film was safe– and that the film should be required instead of the tablet form of Suboxone, placing future generics at a great disadvantage.  It is especially impressive that RB accomplished this feat after selling a million units of the tablets themselves!  I can picture the person making the point:  ‘the tablet is unsafe…. Starting NOW!’

I’m going to write all night if I don’t wrap this up.  To summarize, the Bloomberg article below describes why RB is winning the battle with generics, but the writers of the article, along with most doctors, miss the bigger issue– that misplaced fears, intellectual laziness, and misinformation have protected Suboxone sales from a much greater foe-– generic buprenorphine.  If doctors, states, and insurers ever get their acts together and prescribe according to science, brand name Suboxone profits will go down the toilet faster than the cleaning products made by RB.

The Bloomberg piece:

Reckitt Benckiser Kicks Heroin Tablet Habit With Film: Retail

By Clementine Fletcher

Reckitt Benckiser Group Plc may be kicking its heroin problem.

After losing U.S. patent protection in 2009 for its Suboxone tablet, designed to help heroin users quit, Reckitt Benckiser has said that the entrance of a generic competitor could erode pharmaceutical sales and profit by 80 percent (note by JJ:  What a shame?!  Consider the benefit of such a price reduction for addicts in need of treatment!).

Reckitt Benckiser, which gets most of its revenue from selling home and personal-care products like Lysol cleaners and Durex condoms, has faced calls to sell the business before a generic comes to market. Instead, the London-based company aims to divert the showdown by switching users to a film form of the drug — one whose last patent doesn’t run out until 2025 (note by JJ:  NOW do you see why they made the film?!)

To get people to make the switch, Reckitt Benckiser is thinking more like a consumer company than a pharmaceutical one. It’s drawing on a marketing technique first pioneered by Coca- Cola Co. more than 100 years ago: coupons. By offering up to $45 a month toward a user’s co-payment in the U.S., the company is making the film version, which looks like a Listerine Pocketpak, close to free. That offers patients who get part of the bill subsidized by health insurance little incentive to transfer to a generic pill once it appears on the market.

“They’ve done a good job of making a silk purse out of a not very compelling situation,” said Martin Deboo, an analyst at Investec Securities Ltd. in London.

Reckitt Benckiser’s shares have risen 55 percent in the last five years, outpacing Unilever and Procter & Gamble Co. Under Chief Executive Officer Bart Becht, who stepped down last month, the company more than doubled sales in a decade. The stock has dropped 3.7 percent this year, compared with Unilever’s 4.7 percent gain and P&G’s 1.2 percent gain.

Drugs Growth

The company is due to report third-quarter results tomorrow and will probably say revenue adjusted for purchases and asset sales rose 7 percent at the drugs division, analysts led by Andy Smith at MF Global in London estimate, compared with a 3.9 percent increase for the rest of the business. Profit likely rose 0.9 percent to 430 million pounds, they said.

The film version of Suboxone, introduced in September 2010, accounted for 41 percent of the drug’s U.S. sales by the end of the first half (note by JJ:  Thanks, Wisconsin Badgercare!). That surpassed the company’s own expectations, Becht said on an Aug. 30 conference call arranged by Sanford C. Bernstein. Becht was succeeded by Rakesh Kapoor, a company veteran.

Generic Delay

The film “has been a phenomenal success,” Becht said, according to a transcript of his remarks. “To make the business completely sustainable, we would like to have a share which is clearly much higher than where we are.” He added that the company aims to grow that share every month.

Right now, time is on his side. Teva Pharmaceuticals Industries Ltd., the world’s biggest maker of generics, began the year saying it might launch a Suboxone copy in 2011. Now the company has backed off, saying it no longer expects the product to win regulatory approval this year.

Biodelivery Sciences International Inc., another drugmaker going after Suboxone, said a study comparing its own version of the drug to a placebo failed to show a statistical difference in the treatment of chronic pain. A test in patients addicted to opioids, which include heroin and codeine, is scheduled to begin
later this year. Titan Pharmaceuticals Inc. on Aug. 31 said it’s preparing to seek approval of an upper-arm implant that would deliver buprenorphine, one of
the active ingredients in Suboxone, directly into the bloodstream (note by JJ:  the ONLY active ingredient in Suboxone!)

‘Massive Benefit’

“This delay has been a massive benefit,” said Andrew Wood, an analyst at Sanford C. Bernstein. “With every day that goes by, RB has an extra day to convert users.” Suboxone is either harder-than-expected to copy or generic-drug makers are having second thoughts about targeting addicts, according to Bernstein.

About 1 million people in the U.S. are addicted to heroin, the National Institute on Drug Abuse estimates. As many as 325,000 people use Suboxone to quit the drug or painkillers, says Pablo Zuanic, an analyst at Liberum Capital in London.

The medicine combines buprenorphine, a painkiller derived from the opium poppy that shares some of its properties, with naloxone, a chemical that blunts
withdrawal symptoms (note by JJ:  This is simply WRONG.  BLATANTLY WRONG.  Really–  an opioid antagonist BLUNTING withdrawal symptoms?  Shame on the writers!). The film sells for about $4.63 to $8.23 a dose at Walgreens stores, according to Liberum, depending on its strength and pack size. That means the strongest dose costs about $247 a month.  (note by JJ—a pharmacy near my practice sells generic buprenorphine dissolvable tabs, 8 mg, for $2.33 per tablet—a medication that works EXACTLY the same way IF NOT INJECTED INTRAVENOUSLY)

More than half of people on Suboxone use private insurance with co-pay, Zuanic says. Reckitt Benckiser offers $45 towards co-pay for the film, he said, meaning an insured patient who’d contribute $50 to the cost of the drug may end up spending $5.

‘Near Zero’

“The actual cash cost for some patients buying the film with private insurance could be near zero,” Zuanic said in a note to clients this month. (note by
JJ:  but we are all paying the cost in higher insurance premiums, and some insurers, notably Humana, have draconian policies that stop covering—forcing instant withdrawal- if a patient receives a prescription for a sleep medication such as Ambien, so many people are left paying cash).

Meantime, Suboxone is only becoming more important to Reckitt Benckiser. The drugs division, whose sales grew five times as quickly as the main business last year, accounted for almost 9 percent of sales and 24 percent of profit, up from 7.6 percent and 20 percent in 2009. Sales at the unit will probably rise 12 percent to 829 million pounds ($1.3 billion) this year, according Nomura International Plc estimates.

The maker of French’s mustard is even considering making an injectable Suboxone and developing new products for cocaine, alcohol and cannabis addicts.
The plan has met skepticism.

“We’re quite a long way from having any visibility on these products,” said Julian Hardwick, an analyst at Royal Bank of Scotland Group Plc in London. “Are they products that will work? Which will get approval?”

Prescription drugs are perceived as a bit of a misfit in the home of Vanish stain removers and Finish dishwasher tablets.

Misfit

“Reckitt Benckiser is basically a home and personal-care company with over-the-counter pharmaceuticals,” said Carl Short, an analyst at Standard & Poor’s in London. The drugs unit is “always going to be something that looks like it doesn’t fit with the rest.”

Reckitt Benckiser may look at selling the unit, which Becht himself has said is “not the No. 1 strategic part” of the company, once a generic form of Suboxone reaches pharmacy shelves, analysts said. (note by JJ:  i.e. after all of the profit has been wrung from suffering addicts).  But the company’s marketing savvy, coupled with delays in the launch of a generic, are giving Kapoor time to settle into his new job.

“This is a big job and he is coming in after someone’s done it for some considerable time and very well,” said Julian Chillingworth, who helps manage about 16 billion pounds in shares at Rathbone Brothers Plc, including Reckitt stock. “You wouldn’t want to come in as a CEO into a very successful business and start selling things off on the cheap.”

Not Time

Analyst valuations range from 2 billion pounds to 6.3 billion pounds, according to four estimates compiled by Bloomberg News. Estimates diverge because it’s hard to value the business without knowing how Suboxone sales will resist the generic challenge and whether the shift to film can counter some of that impact.

“Until you get generic competition for the tablet, I think it’s unlikely that prospective buyers would give you the full value for the business,” said Hardwick of RBS. “Now is not the time to sell.”

–With assistance from Naomi Kresge in Berlin. Editors: Celeste Perri, Marthe Fourcade.

This is not all that new, but it was just pointed out to me recently and I figure many of you will find it interesting.  As most readers know, the receptors that mediate the actions of cocaine are completely different than the receptors that are activated during use of opioids.  I will be posting related information in the next few days.

From DataMonitor:

Alkermes, Inc., an integrated biotechnology company, has announced positive topline results from a Phase I clinical study of an investigational combination of ALKS 33 and buprenorphine, an existing medication for the treatment of opioid addiction, for the treatment of cocaine addiction.

Data from the study showed that the combination therapy was generally well tolerated and sublingual administration of ALKS 33 effectively blocked the agonist effects of buprenorphine. Based on these positive results, Alkermes expects to initiate a phase IIa study of the combination therapy in the first half of calendar year 2011, the company said.

The phase I study was a randomized, double-blind, multi-dose,placebo-controlled clinical trial that assessed the safety, tolerability and pharmacodynamic effects of the combination of ALKS 33 and buprenorphine when administered alone and in combination to 12 opioid-experienced users.

Buprenorphine is used for the treatment of opioid addiction, despite its own potential for abuse. Combining ALKS 33, an opioid modulator, with buprenorphine, a partial opioid agonist, may block the agonist effects of buprenorphine thereby reducing the potential for the development of opioid dependence while still maintaining effective therapeutic action. Furthermore,
the pharmacologic properties and low dose of ALKS 33 required to effectively block mu opioid receptors may allow for a co-formulation with buprenorphine as a single sublingual tablet, the company added.

Elliot Ehrich, chief medical officer of Alkermes, said: “We look forward to continuing the recent momentum in our R&D efforts by initiating a phase IIa clinical trial to generate further data, as we advance the ALKS 33 and buprenorphine combination therapy as part of Alkermes’s growing pipeline of proprietary product candidates.”

I just wrote a note to a friend who works in the molecular sciences– she has been studying opioid receptors since the early 1980′s, when things were just getting started on a molecular level.  I’m keeping her name to myself, but I’ll share a few thoughts about what is needed to advance the treatement of opioid dependence– and make a few million dollars along the way (are you listening, RB?)

Hi ——,

(private chit chat that would bore everyone)

Anyway, today I realized what is needed in order to take partial agonist treatment of opioid dependence to the next level.

The problem with buprenorphine is that the ‘ceiling effect’ occurs at a relatively high tolerance level, approximately equal to 40 mg of methadone.  That causes at least two problems.  First, going off Suboxone is a lot of work, as the person still has a great deal of withdrawal to go through.  That may be a good thing early in the process, as it may help keep people on Suboxone, but after a year or so, when people want to try going off the medication, it is a major barrier that opens the floodgates to those old memories of using, etched in the emotions associated with withdrawal.

The second problem with the high ceiling/tolerance level is that surgery is a hassle.  People needing surgery need HIGH amounts of oxycodone to get any analgesia—I usually give 15-30 mg every 4 hours.  Pharmacists shudder to release those doses, and some surgeons and anesthesiologists balk.

The horizontal part of the dose/response curve is the essential part of buprenorphine;  that is what tricks the brain into ‘thinking’ that nothing is wearing off, and in that way eliminating cravings.  But that flat dose/response relationship could occur at lower tolerance levels and still work the same way.

Since I’m wishing for the moon, a series of molecules with progressively lower ceiling levels would be ideal, with the last molecule in the series being Naltrexone.  Although actually, naltrexone doesn’t work—it has NO mu agonism, so there is no tricking of the brain, and no reduction of cravings.  We would want something close to naltrexone, but with a tiny bit of opioid activity that does not vary with dose.

A shorter half-life would also be helpful.  Preparing for surgery requires weeks to get the buprenorphine out of the system.  Of course a shorter half-life means it is easier to get around buprenorphine by people who want to play with agonists, so again, these new molecules would be intended as ‘step down’ meds from early-stage buprenorphine treatment.

Do we know enough about molecular actions at the mu receptor to design molecules with these properties?  Or are we still at the point of making somewhat random changes and assaying the result?  Do you know of any labs doing this type of work?

I figured you’re the person to ask!

Thanks ——–

Jeff

I have been kicking these observations around for the past year, and have been unable to find a big fish willing to ‘bite’.  I truly believe that the observations below have the potential to dramatically change the approach to opioid treatment of chronic pain.  Since I have a blog, I have a soapbox– so I’ll share the idea, and welcome comments in return.  I do ask that proper attribution be provided if this article is shared.

Introduction:

Long-term opioid analgesia without tolerance, respiratory depression, or euphoria?  Introducing the Holy Grail for chronic pain treatment!

Premise:

The miracle of opioid pain relief is fatally limited by tolerance, addiction and respiratory depression.  Buprenorphine, when combined with a mu agonist, results in game-changing effects.  Patients experience potent, dose-related analgesia from the agonist, but have NO euphoria.  The therapeutic window is widened.  Patients unable to control their use of a mu agonist alone gain that control when on buprenorphine. And most exciting, buprenorphine indefinitely anchors tolerance, maintaining analgesia WITHOUT DOSE ESCALATION. This finding offers huge implications for pain management.

Discussion:

Use of opioids for chronic pain has severe limitations.  Tolerance removes the benefits of opioid analgesics over time.  Worse, tolerance is associated with dependence and withdrawal.  Many patients use additional doses of their prescription early in the month, then suffer through withdrawal while awaiting refills.  Others find opioids through less-reliable, non-clinical sources.

At the same time, addiction to mu opioids is a nationwide epidemic.  Reformulation Oxycontin has pushed many opioid users toward diacetylmorphine—brand name Heroin.  Some physicians recommend avoiding mu opioids altogether for chronic pain (e.g. Physicians for Responsible Opioid Prescribing), while pain treatment advocates argue to ease narcotic restrictions.

Over the past six years I have treated over 500 patients using buprenorphine, mostly for opioid dependence.  Buprenorphine, a partial mu agonist, is the active ingredient in Suboxone, a medication used for treating opioid dependence. The majority of my patients began their addictions with narcotics prescribed by doctors for back pain, knee pain, shoulder pain, fibromyalgia, chronic headaches, and other conditions.

Many of my patients found their pain reduced or gone after stopping mu agonists and substituting buprenorphine.  Buprenorphine has the mu activity of 40 mg of daily methadone, but this activity is unlikely responsible for significant analgesia, since patients rapidly become tolerant to the agonist actions of buprenorphine. Instead, their pain while on mu agonists was likely maintained by psychological forces.

Patients on buprenorphine occasionally need opioid analgesia, just like other patients.  My patients have had knees replaced, gallbladders removed, hysterectomies and c-sections, rotator cuff repairs, and in two cases, cardiac surgery.  In all cases, sufficient analgesia was provided by maintaining daily buprenorphine at 4-8 mg per day, and using potent mu agonists, usually oxycodone, in doses ranging from 15-45 mg every 4-6 hours as needed.

Several patients have severe chronic pain from avulsion of the brachial plexus, failed spinal fusion, or other conditions, where prior opioid use resulted in rapid tolerance that prevented effective analgesia. These patients are now successfully maintained on combinations of buprenorphine plus mu agonists.

The combination of buprenorphine plus mu agonists has provided perioperative analgesia for patients on buprenorphine.  Patients universally describe adequate pain relief, even after major surgeries.  They also described the absence of euphoria, and to their surprise, the ability to control their use of pain medication—something impossible before taking buprenorphine.

But it is the effects on chronic pain that suggest a ‘game-changer’ for pain treatment.  Even after over a year on combination buprenorphine/oxycodone, my patients 1. have no euphoria;  2. are often able to manage their own narcotic medication; and most important, 3. describe stable analgesia WITHOUT agonist dose escalation.

The ability to treat pain long-term without tolerance or dose-escalation is as exciting a development as was the initial discovery of opioids for pain relief!

Properties of a combination agent

Buprenorphine is administered sublingually, and could be prescribed as a separate medication, and use verified through urine monitoring.   But greater safety benefits would come through regulations requiring buprenorphine (or a similar partial agonist) to be an inseparable part of every opioid prescription.  Such a policy would dramatically lower the addictiveness and reduce the respiratory depression of mu agonists WITHOUT removing efficacy.  The most obvious formulation would be a transdermal system that delivers buprenorphine and fentanyl, since both are already available in separate transdermal systems.

There may be situations, for example hospice care, where euphoria would be a desirable part of opioid treatment.  But for other cases, analgesia without euphoria has obvious benefits.

I have written to several pharmaceutical companies with this idea, and have heard back that while the idea is interesting and scientifically sound, the generic nature of the component medications reduce the potential for profit that would motivate development.  But given the potential value of this approach for multiple problems– addiction and chronic pain among them—I have to think that there is money to be made—not to mention the advances in treatment that the approach offers.

Reference:

Some supporting background information can be found in:  Alford, D., P Compton, and J Samet, Acute Pain Management for Patients Receiving Maintenance Methadone or Buprenorphine Therapy.  Ann Intern Med. 2006 January 17; 144(2): 127–134.

I also discuss this approach to pain treatment in my ‘Users Guide to Suboxone’, sold on Amazon and at bupeguide.com

Jeffrey T Junig MD PhD

Please do not reproduce without attribution.

Weeks ago I posted a few new ideas—things like a memorial wall for victims of opioid dependence, and a ‘wall of shame’ for doctors who are known for reckless prescribing of opioids.  I mentioned these ideas over at SuboxForum as well.

I received good feedback from readers here, and from members there.  Sometimes the best feedback is the hardest to hear;  I’ll get excited about a certain plan of action, and like anyone, I don’t like it when someone rains on my parade.

One of my addiction docs from years ago was big on ‘sober thinking.’  Back then, it seemed as if anything I came up with that pushed the boundaries was in need of more ‘sober thinking.’  I wondered if ‘sober thinking’ was simply code for ‘I don’t want to say yes to your idea, and maybe that was the case in SOME instances.  But I now recognize a part of myself that acts quickly, impulsively, with great optimism, and with little regard for risks.  ‘Sober thinking’ is simply letting an idea sit in one’s mind for a few days or even weeks, and keeping a truly open mind to the comments that one receives about the idea.

Beats Death--- Barely

I won’t spell out who wrote to me, but I’ll thank the people who did—who risked my ire by giving their honest opinions.  I mentioned a memorial page;  some people pointed out that a memorial on an addiction-related web page may add to the pain and shame felt by family members.  As for my ‘doctor wall of shame’, I was reminded that every story has two sides, and it may be more useful to simply provide referenced information that would allow readers to make up their minds without my own coloring of the facts.  I want to thank the people who wrote, and let them know that they made a difference—and the site will be better because of their efforts.

Instead of the earlier ideas, I added what I am calling the ‘consequences’ page.  The page will contain news stories identified to Google as having ‘drug overdose’ in their tags.  The information will be replaced every 24 hours or so.  I experimented with a couple different intervals and found that no day went by without a significant amount of news under that tag—a rather compelling statistic!

Click on ‘consequences’ to check it out, and let me know what you think!

More than ever, patients have easy access to information once read only by scientists and medical professionals.  And at the same time, doctors have reduced the time spent with patients during appointments.  The result has been an increase in internet-educated patients, who come to appointments armed with data from package inserts, information from internet health forums, and stacks of questions from net-savvy relatives.

There is a good side to this process, of course.  Patients are wise to take greater interest in their personal health, and to be knowledgeable of medications that they are taking.  And whether good or bad, the situation is necessary, given the abdication by many physicians of their roles as educators.

But there are downsides to the situation as well.  Package inserts provide studies and odds ratios for the risks from medications, but interpreting the studies and odds ratios requires education and experience. Some data is reported in a way that a person without considerable education in statistics would have a hard time deciphering what is or isn’t relevant.  Some patients struggle under the burden of calculating and weighing risks, and prefer to have a careful, caring doctor provide his/her opinion whether a medications is safe or not.  Speaking from my role as physician, I am frustrated when patients choose to follow advice from an online forum over a recommendation based on medical knowledge or a careful literature search..

Doctors sometimes add to the problem.  I am frustrated when doctors make claims that are not supported by best medical practice or by medical science.  Distinctions between sources of information are blurred, so that some ‘facts’ are based on nothing but rumor.  The process is like the old ‘telephone line’ game; a doctor reads a question about a medication or illness, and responds with his/her opinion.  Another doctor then hears or reads that answer, adopts it as fact, and shares it with other doctors—who then reinforce the ‘factual’ nature of the information.

People tend to take information from physician educators/writers verbatim, as if the act of putting information online, in writing, guarantees that it to be true.  People are confused when they read conflicting ‘facts’ or recommendations from people with comparable credentials.

I try, when writing here, to differentiate between facts, best medical practice, and personal opinion.  If someone asks ‘how long should I stay on Suboxone?’, I’ll reply that several studies show high relapse rates in people who stay on Suboxone for less than 6 months (fact), that more and more physicians are keeping patients on the medication long-term (medical practice), and that in my opinion, many people are best off staying on the medication for an extended period of time.  You get the idea.

I think it is because of my PhD training that I tend to take a closer look at things that everyone ‘knows’ and ask, ‘says who?’  History has given us many examples of things that everyone knew that turned out to be wrong—from the connection between autoimmune disease and breast implants that wasn’t, to global cooling, the impending disaster when I was a kid (read here)—and we all know how THAT turned out!

The treatment of opioid dependence with buprenorphine/Suboxone appears to be particularly vulnerable to misinformation.  Some examples:

The naloxone in Suboxone prevents the person from getting ‘high’: Naloxone is not active orally or sublingually, and is added to Suboxone to prevent intravenous injection of the medication.  Confusion comes in part from mistaking naloxone, an IV medication, with naltrexone, an orally-active medication that is NOT part of Suboxone.

People will abuse Subutex because it doesn’t have the opioid blocker in it: Subutex or the generic equivalent—buprenorphine—works just like Suboxone when taken correctly.  Doctors and pharmacists are mistaken when they believe that buprenorphine is more addictive if naloxone is not included.  In reality, the subjective effects of Suboxone and Subutex are identical.  There IS a relatively low incidence of intravenous abuse of buprenorphine;  Suboxone in theory causes withdrawal if injected because of the presence of naloxone.  Realize, though, that the effects of buprenorphine or Suboxone are similar, whether injected or taken correctly.  Injected buprenorphine has the same ‘ceiling effect’ as does sublingual buprenorphine, and so people on buprenorphine maintenance would NOT experience an opioid ‘high’ after injecting their medication—any more than they do when taking it sublingually.

The tablet should not be crushed or chewed: The package insert recommends that Suboxone tablets should be taken sublingually, without crushing the tablet.   I am guessing that the recommendation comes out of an attempt to standardize the bio-availability of buprenorphine.  Studies show that as little as 15% of a dose of buprenorphine is absorbed, and in my opinion, the high cost of the medication warrants efforts to reduce the amount that gets wasted.  The bio-availability is affected by the concentration of buprenorphine in saliva, the surface area available for absorption, and the time that the medication is in contact with absorptive surfaces.  Passage of buprenorphine through mucous membranes is the rate-limiting step for absorption–NOT dissolution of the tablet.  In other words, crushing or chewing the tablet does NOT cause a ‘high’, and is NOT a sign of drug-seeking behavior.  Neither does crushing or chewing hasten the onset time of a dose of Suboxone.

Discussions about chewing or crushing buprenorphine provide examples of the doublespeak that only confuses people.  My own recent discussion with another Suboxone prescriber went like this: “I don’t want patients to crush or chew the tablet because that will make it get absorbed too quickly.  In fact,  I usually recommend the film, because it dissolves much more quickly than the tablet.”  Say what?  Do we want it to dissolve more quickly or not?  The truth is that it really does not matter.  The dissolving of buprenorphine— or the film– is the LONG part of the process.

The veins under the tongue absorb the drug in Suboxone. Actually, buprenorphine passes through all of the surfaces in the mouth, eventually entering capillaries under the surface.  The veins under the tongue absorb little or no buprenorphine.

You must stop smoking cigarettes if you are on Suboxone: I have searched the literature and I have talked to folks at Reckitt Benckiser, and I can find no evidence to back up this claim.  Scientifically, I cannot think of a reason that cigarette smoking would affect the absorption of buprenorphine, except perhaps to increase production of saliva, diluting the buprenorphine in solution and reducing diffusion into tissues.  I doubt this would have any significant effect on the bio-availability of buprenorphine, and my clinical experiences backs that up.  Patients in my practice who smoke have had normal responses to buprenorphine or Suboxone.

You can’t take pain pills if you are on Suboxone: Actually you can, but they will only reduce pain if the dose is sufficient.   I often use this approach to treat people on buprenorphine who undergo surgery.  But problems ARE caused if a person does things in the opposite order.  In that case—if someone taking opioid agonists then takes buprenorphine– there is risk that the person will develope precipitated withdrawal, depending on the amount of opioid agonist that was being used.

The longer you are on Suboxone, the harder it is to stop: I have read no studies supporting this oft-read comment, and I can think of NO reason that it would be true.  The tolerance to buprenorphine is set by the ceiling effect of the drug, and once tolerance develops, typically by several weeks on the medication, longer periods of time do not push tolerance higher.

The film formulation is safer than the tablet. Says who? If we are worrying about kids getting their hands on Suboxone, yes—the little orange tablets look like candy to a toddler.  But little red strips of flavored material appear appetizing as well. ALL medications should be kept away from children.  If the safety concerns are directed toward patients—for example one doctor told me he prescribes the film because it cannot be crushed—remember that crushing Suboxone is not a problem.  I SUSPECT (only my opinion) that the change in formulation was a marketing ploy aimed toward preventing acceptance of generic buprenorphine tablets.  Reckitt Benckiser apparently convinced the state of Wisconsin to cover the film exclusively, rather than allow addicts the choice of taking generic buprenorphine—a medication that works exactly the same as Suboxone, at about half the cost.

I think you get the idea.  Whether thinking about Suboxone or another medication, I urge readers to always ask the question, ‘says who?’  There are MANY experts out there on the internet—and some exhibit more restraint in their comments than others.  Ask yourself, what is the mechanism for what is being described?  And if it doesn’t seem to make sense, consider that just perhaps, you’re the right one.

I’ll often joke with others who have histories of addiction over the ingenuity of addicts when it comes to finding or using drugs.  If that amount of creativity and work ethic were ever harnessed for legitimate reasons, the opportunities would be limitless!

I have similar thoughts when I read the story about several county inmates at a New Jersey jail, who smuggled Suboxone into jail disguised as watercolor paint on cartoon images!

Dope Smugglers

The story has a humorous side, of course– but after we stop laughing, we are all sobered by the memories of the living hell created by opioids, detox, and withdrawal.  I’ve met many, many people who went through detox in jail or prison, and I realize that being in such a state is no laughing matter.  I assume that the experience of withdrawal in prison is about as bad as things get;  an experience that will never be part of someone’s bucket list!

The story also reminds us that buprenorphine is a very potent opioid.  One tablet of Suboxone contains 8000 micrograms of buprenorphine– enough to provide about 100 ‘hits’ of 80 micrograms each, which would have significant effects in people not tolerant to opioids. The illicit use of tiny doses of Suboxone–yet significant doses of buprenorphine– has become the most troublesome avenue for diversion of buprenorphine. This diversion is one reason for keeping prescribed doses to only the amount necessary to block receptors– which in the vast majority of people is 16 mg or less.

I just had a thought on a different topic… do you think we will ever get to the point of seeing addiction as a disease, where people who are sick, depressed, and dehydrated from withdrawal, in prison, would be treated in a way that reduces their misery?

Now THAT’S funny!  Sort of…