Uncoupling Mu-Receptor Analgesia,

Tolerance, and Euphoria

Modification of agonist effects using

buprenorphine

Jeffrey T Junig MD PhD

Fond du Lac Psychiatry

Asst. Clinical Professor of Psychiatry

Medical College of Wisconsin

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Content of Activity: ASAM Medical –Scientific

Conference 2012

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Forest Labs Speaker Bureau $2000 Speaking fees

Opium: A History. by Martin Booth c.3400 B.C. The opium poppy is cultivated in lower Mesopotamia. The Sumerians would

soon pass along the plant to the Assyrians, from the Assyrians to the Babylonians, in turn

to the Egyptians.

c.1300 B.C. In the capital city of Thebes, Egyptians begin cultivation of opium

thebaicum, grown in their famous poppy fields. The opium trade flourishes during the reign

of Thutmose IV, Akhenaton and King Tutankhamen. The trade routes included Greece,

Carthage, and Europe.

c. 460 B.C. Hippocrates, "the father of medicine", dismisses the magical attributes of

opium but acknowledges its usefulness as a narcotic and styptic in treating internal

diseases, diseases of women and epidemics.

330 B.C. Alexander the Great introduces opium to the people of Persia and India.

A.D. 400 Opium thebaicum, from the Egyptian fields at Thebes, is first introduced to China

by Arab traders.

400 AD

1200 AD Opium treats diarrhea

1600 Portuguese smoke opium1780 Persians drink opium

1803 Friedrich Sertürner invents morphine

1903 heroin use rises dramatically; US passes Pure Food and Drug Act requiring labels on patent medications; heroin availability decreases

1874 Heroin first synthesized by C. R. Wright

1972 Snyder and

Pert discover

opiate receptor

1975 Kosterlitz and

colleagues isolate an

endogenous opioid in the

brain, enkephalin2003 crackdown on online pharmacies

February 2009 FDA announces

plans further to restrict access to

opioid-based pain-relievers

March 2009 World Health

Organization: 80% of the world’s

population lacks access to pain

relief. Human Rights Watch

blames “over-zealous drug control

efforts”.

3400 BC-1300 BC opium spreads from Mesopotamia through Greece and Europe

1200 AD Opium treats diarrhea

1874 Heroin first synthesized by C. R. Wright

1972 Snyder and Pert discover opiate

receptor

DATA 2000

A.D. 1200 Ancient Indian medical treatises describe the use of opium for diarrhea

and sexual debility.

1300s Opium disappears for two hundred years from European historical record.

Opium had become a taboo subject for those in circles of learning during the Holy

Inquisition. In the eyes of the Inquisition, anything from the East was linked to the

Devil.

1500 The Portuguese, while trading along the East China Sea, initiate the smoking

of opium. The effects were instantaneous as they discovered but it was a practice the

Chinese considered barbaric and subversive.

1527 During the height of the Reformation, opium is reintroduced into European

medical literature by Paracelsus as laudanum.

1600s Residents of Persia and India begin eating and drinking opium mixtures for

recreational use.

1601 Ships chartered by Elizabeth I are instructed to purchase the finest Indian

opium and transport it back to England.

1620s -1670s Opium becomes the main commodity of British trade with China.

1680 English apothecary, Thomas Sydenham, introduces Sydenham's Laudanum, a

compound of opium, sherry wine and herbs. His pills become popular remedies for

numerous ailments.

1700 The Dutch export shipments of Indian opium to China and the islands of

Southeast Asia; the Dutch introduce the practice of smoking opium to the Chinese.

1729 Chinese emperor, Yung Cheng, issues an edict prohibiting the smoking of opium

and its domestic sale, except under license for use as medicine.

1750 The British East India Company assumes control of Bengal and Bihar, opium-

growing districts of India. British shipping dominates the opium trade out of Calcutta to

China.

1753 Linnaeus, the father of botany, first classifies the poppy, Papaver somniferum -

'sleep-inducing',

1767 The British East India Company's import of opium to China reaches a staggering

two thousand chests of opium per year.

1796 The import of opium into China becomes a contraband trade. Silver was

smuggled out to pay for smuggling opium in.

1799 China's emperor, Kia King, bans opium completely, making trade and poppy

cultivation illegal.

1803 Friedrich Sertürner discovers the active ingredient of opium by dissolving it in

acid then neutralizing it with ammonia. The result: morphine.

Physicians believe that opium had finally been perfected and tamed. Morphine is

lauded as "God's own medicine" for its reliability, long-lasting effects and safety.

1812 American John Cushing, under the employ of his uncles' business, James and

Thomas H. Perkins Company of Boston, acquires his wealth from smuggling Turkish

opium to Canton.

1816 John Jacob Astor of New York City joins the opium smuggling trade. His

American Fur Company purchases ten tons of Turkish opium then ships the

contraband item to Canton on the Macedonian. Astor would later leave the China

opium trade and sell solely to England.

1819 Writer John Keats and other English literary personalities experiment with opium

intended for strict recreational use - simply for the high and taken at extended, non-

addictive intervals

1827 E. Merck & Company of Darmstadt, Germany, begins commercial manufacturing of

morphine.

1830 The British dependence on opium for medicinal and recreational use reaches an all

time high as 22,000 pounds of opium is imported from Turkey and India.

1837 Elizabeth Barrett Browning falls under the spell of morphine. This, however, does

not impede her ability to write "poetical paragraphs."

March 18, 1839 Lin Tse-Hsu, imperial Chinese commissioner in charge of suppressing

the opium traffic, orders all foreign traders to surrender their opium. In response, the

British send expeditionary warships to the coast of China, beginning The First Opium War.

1841 The Chinese are defeated by the British in the First Opium War. Along with paying a

large indemnity, Hong Kong is ceded to the British.

1843 Dr. Alexander Wood of Edinburgh discovers a new technique of administering

morphine, injection with a syringe. He finds the effects of morphine on his patients

instantaneous and three times more potent.

1874 English researcher, C.R. Wright first synthesizes heroin, or diacetylmorphine, by

boiling morphine over a stove.

In San Francisco, smoking opium in the city limits is banned and is confined to

neighboring Chinatowns and their opium dens.

1890 U.S. Congress imposes a tax on opium and morphine.

1895 Heinrich Dreser finds that diluting morphine with acetyls produces a drug without

the common morphine side effects. Bayer begins production of diacetylmorphine and

coins the name "heroin."

Early 1900s The philanthropic Saint James Society in the U.S. mounts a campaign to

supply free samples of heroin through the mail to morphine addicts who are trying give

up their habits.

1902 In various medical journals, physicians discuss the side effects of using heroin as a

morphine step-down cure. Several physicians would argue that their patients suffered

from heroin withdrawal symptoms equal to morphine addiction.

1903 Heroin addiction rises to alarming rates.

U.S. Congress passes the Pure Food and Drug Act requiring contents labeling on patent

medicines by pharmaceutical companies. As a result, the availability of opiates and

opiate consumers significantly declines.

1948-1972 Corsican gangsters dominate the U.S. heroin market through their

connection with Mafia drug distributors. After refining the raw Turkish opium in

Marseilles laboratories, the heroin is made easily available for purchase on New York

City streets.

1950s U.S. efforts to contain the spread of Communism in Asia involves forging

alliances with tribes and warlords inhabiting the areas of the Golden Triangle, (an

expanse covering Laos, Thailand and Burma), thus providing accessibility and

protection along the southeast border of China. In order to maintain their relationship

with the warlords while continuing to fund the struggle against communism, the U.S.

and France supply the drug warlords and their armies with ammunition, arms and air

transport for the production and sale of opium. The result: an explosion in the

availability and illegal flow of heroin into the United States and into the hands of drug

dealers and addicts.

1965-1970 U.S. involvement in Vietnam is blamed for the surge in illegal heroin being

smuggled into the States. To aid U.S. allies, the Central Intelligence Agency (CIA) sets

up a charter airline, Air America, to transport raw opium from Burma and Laos. As well,

some of the opium would be transported to Marseilles by Corsican gangsters to be

refined into heroin and shipped to the U.S via the French connection. The number of

heroin addicts in the U.S. reaches an estimated 750,000.

October 1970 Janis Joplin, is found dead at Hollywood's Landmark Hotel, a victim of an

"accidental heroin overdose."

1972 Solomon Snyder and Candace Pert discover opiate receptor in the brain.

Mid-1970s Saigon falls. The heroin epidemic subsides. The search for a new source of raw

opium yields Mexico's Sierra Madre. "Mexican Mud" would temporarily replace "China White"

heroin until 1978.

1975 Hans Kosterlitz and his colleagues isolate and purify an endogenous opioid in the brain,

enkephalin

1978 The U.S. and Mexican governments find a means to eliminate the source of raw opium

- by spraying poppy fields with Agent Orange. In response, another source of heroin is found

in the Golden Crescent area - Iran, Afghanistan and Pakistan, creating a dramatic upsurge in

the production and trade of illegal heroin.

1982 Comedian John Belushi of Animal House fame, dies of a heroin-cocaine - "speedball"

overdose.

1992 Colombia's drug lords are said to be introducing a high-grade form of heroin into the

United States.

1993 The Thai army with support from the U.S. Drug Enforcement Agency (DEA) launches its

operation to destroy thousands of acres of opium poppies from the fields of the Golden

Triangle region.

January 1994 Efforts to eradicate opium at its source remains unsuccessful. The Clinton

Administration orders a shift in policy away from the anti- drug campaigns of previous

administrations. Instead the focus includes "institution building" with the hope that by

"strengthening democratic governments abroad, [it] will foster law-abiding behavior and

promote legitimate economic opportunity."

1995 The Golden Triangle region of Southeast Asia is now the leader in opium production,

yielding 2,500 tons annually. According to U.S. drug experts, there are new drug trafficking

routes from Burma through Laos, to southern China, Cambodia and Vietnam.

November 1996 International drug trafficking organizations, including China, Nigeria,

Colombia and Mexico are said to be "aggressively marketing heroin in the United States and

Europe."

1999 Bumper opium crop of 4,600 tons in Afghanistan. UN Drug Control Program estimates

around 75% of world's heroin production is of Afghan origin.

2000 Taliban leader Mullah Omar bans poppy cultivation in Afghanistan; United Nations Drug

Control Program confirms opium production eradicated.

Autumn 2001 War in Afghanistan; heroin floods the Pakistan market. Taliban regime

overthrown.

October 2002 U.N. Drug Control and Crime Prevention Agency announces Afghanistan

has regained its position as the world's largest opium producer.

December 2002 UK Government health plan will make heroin available free on National

Health Service "to all those with a clinical need for it". Consumers are skeptical.

October 2003 US Food and Drug Administration (FDA) and Drug Enforcement

Administration (DEA) launch special task force to curb surge in Net-based sales of

narcotics from online pharmacies.

January 2004 Consumer groups file a lawsuit against Oxycontin maker Purdue Pharma.

The company is alleged to have used fraudulent patents and deceptive trade practices.

September 2004 A Tasmanian company publishes details of its genetically-engineered

opium poppies. mutants do not produce morphine or codeine. Tasmania is the source of

some 40% of the world's legal opiates; its native crop of poppies is already being re-

engineered with the mutant stain. Conversely, some investigators expect that the

development of genetically-engineered plants and microorganisms to manufacture

potent psychoactive compounds will become widespread later in the 21st century.

Research into transgenic psychotropic botanicals and microbes is controversial; genes

from mutants have a habit of spreading into the wild population by accident as well as

design.

October 2004 Unannounced withdrawal of newly-issued DEA guidelines to pain

specialists. The guidelines had pledged that physicians wouldn't be arrested for

providing adequate pain-relief to their patients. DEA drug-diversion chief Patricia

Good earlier stated that the new rules were meant to eliminate an "aura of fear" that

stopped doctors treating pain aggressively.

December 2004 McLean pain-treatment specialist Dr William E. Hurwitz is sent to

prison for allegedly "excessive" prescription of opioid painkillers to chronic pain

patients. Testifying in court, Dr Hurwitz describes the abrupt stoppage of

prescriptions as "tantamount to torture".

May 2005 Researchers at Ernest Gallo Clinic and Research Center in Emeryville,

California, inhibit expression of the AGS3 gene in the core of nucleus accumbens.

Experimentally blocking the AGS3 gene curbs the desire for heroin in addicted

rodents. By contrast, activation of the reward centers of the nucleus accumbens is

immensely pleasurable and addictive. The possible effects of overexpression and

gene amplification of AGS3 remain unexplored.

May 2006 In Mexico, Congress passes a bill legalizing the private personal use of all

drugs, including opium and all opiate-based drugs. President Vicente Fox promises to

to sign the measure, but buckles a day later under US government pressure. The bill

is referred back to Congress for changes.

September 2006The head of the United Nations Office on Drugs and Crime reports

that Afghanistan's harvest in 2006 will be around 6,100 metric tons of opium - a

world record. This figure amounts to some 92% of global opium supply.

1. November 2006 S enior UK police officer Howard Roberts advocates legalization of

heroin and its availability without charge on National Health Service (NHS)

prescription.

August 2007 Afghanistan's poppy production rises an estimated 15 percent over

2006. Afghanistan now accounts for 95 percent of the world's opium poppy crop, a 3

percentage point increase over last year. The US State Department's top

counternarcotics official Tom Schweich claims that Afghanistan is now "providing

close to 95 percent of the world's heroin".

November 2008 Swiss voters overwhelmingly endorse a permanent and

comprehensive legalized heroin program.

February 2009 FDA announces plans further to restrict access to opioid-based

pain-relievers by American citizens and their doctors.

March 2009 According to the World Health Organization, around 80% of the world’s

population does not have adequate access to pain relief. The international

organization Human Rights Watch blames a failure of leadership, inadequate training

of health care workers, and “over-zealous drug control efforts”.

July 2011 Seattle hosts Kappa Therapeutics, dedicated to kappa opioids and

antagonists. Investigators hope that selective kappa opioid antagonists can be used

to treat anxiety disorders, clinical depression, anhedonia, eating disorders,

alcoholism and a variety of substance abuse disorders.

Who Am I?

Jeffrey T Junig MD PhD

PhD Neurochemistry, University of Rochester Center for Brain

Research

MD U of R School of Medicine and Dentistry

Residency in Anesthesiology at Penn, Board Certified Anesthesiologist

Worked in pain clinics for 10 years

Personal opioid dependence– 2001 – treated ‘old fashioned way’

Residency in Psychiatry– Board Certified Psychiatrist

Solo practice; Asst Clinical Professor of Psychiatry, Medical College of

WI

There is no doubt that opioids have been one of the

most important forces behind the advance of

modern medicine.

J Junig, ASAM Annual Meeting 2012

Modern opioids have allowed for the creation of

modern surgical technique, eased suffering, allowed

death with dignity, and relieved pain in countless

situations, big and small.

And yet------

Opioid analgesia is limited by tolerance.

Physical dependence eliminates free use of opioids

Opioids cause euphoria, which removes insight, fueling

addiction.

Respiratory depression from illicit opioid use is a rapidly-

growing cause of death.

Many patients cannot control their own use of opioids

Divisions within the medical community debate the utility of

opioid use for chronic pain.

Motivations of pharmaceutical companies are questions

Growing number of patients taking buprenorphine for

treatment of opioid dependence.

During need for analgesia e.g. trauma or surgery,

recommendations call for lowering dose of buprenorphine

and treating pain using high dosages of opioid agonists,

with careful monitoring of respiratory function.

Can some of the risks of opioids be separated from their benefits?

Buprenorphine for Opioid Dependence

Patients maintained on buprenorphine were given mu opioids for

pain control. Patients included those with acute surgical pain, e.g.

total knee replacement, cholecystectomy, median sternotomy,

hysterectomy, and sinus surgery.

Patients on buprenorphine undergoing surgery experienced adequate

to good analgesia using oxycodone, 15-30 mg every 4 hours, without

subjective euphoria. Patients on PCA, or taking agonists at home,

described being able to control dosing of the agonist, despite

inability to control mu opioid use when not on buprenorphine.

Findings- Acute Pain

Clue– ‘precipitated withdrawal.’ If

a person has a high opioid

tolerance, > 100 mg oxycodone

per day, induction with

buprenorphine will cause

precipitated withdrawal. The

buprenorphine ‘pulls’ tolerance

down to the maximum effect of

the partial agonist, causing

withdrawal as tolerance resets at

that level.

Question: Effects on Chronic Pain?

If surgical-maintained patient is KEPT on

buprenorphine, and given 100-200 mg of

oxycodone per day, the patient experiences NO

withdrawal, provided the buprenorphine is not

discontinued.

Analgesia DOES occur.

But:

Patient 1: 34-y-o Caucasian woman, history of patient foramen

ovale. Trans-venous patch eventually eroded through heart

causing tamponade, open repair complicated by sternal

dehiscence, months in ICU. Discharged eventually on 400 mg

of oxycodone per day. Dose increased for worsening pain in

ribs and sternum; dosed to 600 mg oxycodone per day, then

doctor decided he ‘was not comfortable with case anymore.’

Started on buprenorphine/Suboxone; required months of detox

off high-dose oxycodone.

Initially did well on buprenorphine, but titanium device

fractured and sternum opened, requiring new titanium implant

to be inserted. Maintained on low dose of buprenorphine (4

mg); oxycodone added.

After new implant patient wanted to try buprenorphine for

pain control. EASILY stopped oxycodone; buprenorphine

increased to 16 mg per day. Initially had relief, but relief

dissipated with tolerance. Reduced buprenorphine from 8

mg to 4 mg per day, and given 15 mg oxycodone every 4

hours. Eventually changed to Oxycontin 20 mg TID plus

buprenorphine 4 mg; uses up to 5 mg oxycodone PRN.

Stable on dose for over 2 years; reports ‘best pain relief in

years; takes own meds and controls them; reports pain

relief but no warmth or euphoria.

Patient very happy with outcome.

Patient 2: 22-y-o Caucasian woman developed advanced

scoliosis, had thoraco-lumbar fusion at age 18. Several

years later, repair came apart; surgeon would not help. Has

radicular compression at multiple levels. Using over 600 mg

oxycodone per day, supplementing with IV heroin.

Difficult detox over several months to dose of oxycodone

approximately equal to 100 mg per day, then induced to

buprenorphine. Significant withdrawal precipitated.

Patient started on buprenorphine 4 mg per day, plus

oxycodone 15 mg every 4 hours. Case complicated when

patient’s ‘using’ bf returned onto scene; attempted to keep

medications with patient’s mother.

Patient appeared to be doing well; was working, for

example but always complaining of need for greater relief.

At two month follow-up, urine did not contain

buprenorphine; patient reported that she felt better

without the buprenorphine. We attempted to manage her

pain, but her tolerance rose very quickly, back to the 400-

600 mg of oxycodone per day that she was using before.

She was discharged from our practice for violating terms of

treatment. At that point, she begged to come back, and to

stay on buprenorphine; she insisted that it worked well for

her and she ‘couldn’t explain’ why she stopped the

buprenorphine. She was referred to a different physician.

Patient 3: 24-y-o HS baseball star. Tore rotator cuff in

dominant arm. Arm pulled traumatically from socket on three

occasions. After repair, lidocaine infused into joint for pain

relief; destroyed all cartilage in joint ($ settlement by

company). Chronic, severe ‘bone on bone’ pain in dominant

arm; also brachial plexus compression from scar tissue from

repeated surgeries. Using oxycodone, 200 – 400 mg/day.

Lost his physician for testing positive for marijuana. Offered

to try combined technique. Detoxed over several months,

then started on buprenorphine, 16 mg per day. Pain relief

initially helpful; dissipated over several months, assumedly

from tolerance.

Buprenorphine dose lowed to 4 mg per day, and oxycodone

added– 7.5-15 mg oxycodone every 4 hours as needed.

Patient reports excellent pain relief at 2 years. No dose

escalation. Reports ‘odd analgesia’ without any euphoric

component of opioids.

Also has been able to move forward academically and in

workforce. Controls his own medications– something that

he continues to be surprised by. Anticipates using similar

combination for extended period of time.

Patient 4: 50-y-o executive, Crohn’s disease for 20 years;

allergic to biological therapies. Multiple surgeries and

adhesions. On buprenorphine, but continues to have severe

pain. Was taking buprenorphine from a different physician.

For an acute procedure, we lowed buprenorphine from 8 to 4

mg per dad, and had him use oxycodone for post-op pain. He

appreciated the pain relief to the point that he asked to stay on

combination. Now takes buprenorphine 4 mg, plus Oxycontin

20 mg TID and oxycodone 15 mg every 4 hours as needed,

total of 110 mg oxycodone per day. Believes that his pain

relief is better than in past, and has same reaction– no

euphoria, and no desire to take more than what is needed for

pain.

Patient 5: 42-y-o Caucasian man, tore spinal nerves from

cord during snowmobiling injury. Severe phantom limb pain

with spasms in dominant arm. Taking over 500 mg

oxycodone per day before discharged by his doctor, who was

‘no longer comfortable’ prescribing a high dose of opioid.

Patient self-detoxed (very ill), and started by us on

buprenorphine 16 mg per day. Good pain relief for several

months, then overcome by worsening pain ‘spasms’.

Neurosurgeon placed intracranial stimulator that would

precipitate seizures when turned up– but no pain relief. We

added oxycodone 15 mg every 4 hours, and 2400 mg of

gabapentin per day.

Gabapentin reduced ‘spasms’ dramatically, and oxycodone

largely removed aching and phantom pains. Patient happy

with combination, and as with others, finds less euphoria,

but also less sedation and less cravings, using the

combinations than when using oxycodone alone.

Stable analgesia without dose escalation for past 18

months.

Patients report that pain is relieved, but they are

disappointed by lack of ‘opioid feeling.’

They are surprised that they can make a script

last ‘on time’ for entire month.

Tolerance does not appear to occur, out for 24

months in one patient and 18 months in another.

Dose escalation was easily prevented in all

patients

Analgesia in presence of buprenorphine has unique properties

Place patients on dose of buprenorphine sufficient to

benefit from ‘ceiling effect’ of buprenorphine– to obtain

craving reduction.

Use lowest possible dose of buprenorphine, to avoid

blocking effects of agonists, but that still provides constant

opioid effect to brain receptors.

Add potent opioid agonist (oxycodone) and assess pain

relief, adjusting agonist dosage to find proper level and

then attempt to make few changes in dose going forward.

Technique

Combination opioid treatment with buprenorphine (4 mg per

day) and mu agonists (oxycodone 15-30 mg every 4 hours)

resulted in adequate analgesia. This analgesia was

maintained for up to 24 months without need for dose

escalation. Patients reported the absence of euphoria, and

were in most cases to manage their own prescriptions--

something not possible in the absence of buprenorphine.*

*Patient two discontinued buprenorphine without permission,

and shortly afterward ran out of oxycodone early.

Results

If buprenorphine is stopped, the addictiveness of

the opioid agonist returns.

Dose escalation returns rapidly, and tolerance

appears to develop rapidly as well.

Only way to restart combination is to STOP

agonist first, then induce with buprenorphine.

Restarting buprenorphine will otherwise

precipitate withdrawal.

Stopping buprenorphine?

All patients taking the combination of buprenorphine and

oxycodone described a 'different feeling' to the oxycodone

compared to their experience before buprenorphine. They

reported that while the oxycodone removed their pain, there was

no sense of euphoria from the oxycodone.

Tolerance/dose escalation has always been the major barrier to

long-term opioid analgesia. The partial agonist buprenorphine

appeared to anchor tolerance to the '40 mg methadone' level

known to be the comparative potency of buprenorphine, allowing

for long-term analgesic effects from mu opioid agonists.

Findings

Preliminary investigations suggests that other potent mu agonists

would be appropriate candidates for combination analgesia. For

example, a dual patch method with fentanyl and buprenorphine.

The effects of buprenorphine in mitigating euphoria suggest a role in

affecting the current epidemic of opioid dependence. In other words,

imagine if every opioid agonist was intrinsically attached to

buprenorphine! Opioid dependence is currently at epidemic levels,

and any means to reduce diversion of opioids will save lives.

Combining buprenorphine or other partial agonists with agonists may

be one answer to the opioid dependence problem. Such combinations

may also reduce the risk of addiction for individual patients who are

exposed to potent opioids after surgery.

Findings (cont)

Good evidence that true pain is present

Stable on buprenorphine for at minimum several

months

Evidence for motivation to avoid old life-style, i.e.

sick and tired.

Trustworthy, non-using partner to witness/control

medications

Ideal Cases:

Opioid analgesia is limited by tolerance, addiction and respiratory

depression. Buprenorphine, when combined with a mu agonist, causes

a range of effects. Patients experience dose-related analgesia from the

agonist without euphoria. Patients unable to control their use of a mu

agonist alone gain that control when on buprenorphine. And

buprenorphine appears to anchor tolerance, maintaining analgesia

without dose escalation. This finding offers huge implications for pain

management.

Jeffrey T Junig MD PhD

Fond du Lac Psychiatry

Asst. Clinical Professor of Psychiatry

Medical College of Wisconsin

Summary