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Pain & opioid addiction: hydrocodone update & zohydro: the paradigm for the epidemic .... continues.

Physicians and other healthcare practitioners play an important role in the identification and mitigation of prescription opioid abuse and still have a lot to learn. Many clinicians lack the understanding of how big a problem drug diversion is but significant progress is being made in the education about the paradigm of prescription drug abuse, pain, diversion and addiction. Inadequate knowledge regarding this topic can lead to under vigilance, an obstacle in the way of deterrence; or over vigilance which puts obstacles in the way of legitimate pain relief. We may not be able to control what patients do with our prescriptions nor control over friends and relatives, nor the drugs left over in the medicine cabinet, but we can control what and how we prescribe (www. medscape.com/view article/824702?nIid=56823_2703&s rc=wnl_edit_dail&uac=43207EJ). (1)

There is a wide variation which suggests that in some parts of the nation pain is under treated, while in other places over prescribing occurs despite the high risk of abuse and the current prescription drug abuse epidemic. Physicians and other prescribers of controlled substances must adequately balance treating pain with over prescribing. In 2001, the AMA and 21 other health organizations including the DEA issued a joint statement of accountability that "both healthcare professionals, and law enforcement and regulatory personnel, share responsibility for ensuring that prescription pain medications are available to the patients who need them and for preventing these drugs from becoming a source of harm or abuse," and that "preventing drug abuse is an important societal goal, but there is consensus, by law enforcement agencies, health care practitioners, and patient advocates a like, that it should not hinder patients' ability to receive the care they need and deserve." (2)

Opioids are excellent medications to ease suffering as part of end of life care. They are also effective when prescribed short term in the treatment of acute pain. They don't work well when taken daily for months and years. There is very Utile evidence in the efficacy of treatment in chronic non-cancerous pain. According to the CDC, the over prescribing of opioids for non-cancer pain was the main cause of our nations opioid addiction epidemic http;//america.aljazeera. Com/articles/2013/8/29/painkiller-kill-morepeoplethanmarijuanause. html. Longitudinally overtime, many patients develop tolerance to the analgesic effects, leading to higher doses and often a decline in the quality of life and ability to function. Pain can be made even worse as result of opiate induced hyperalgesia "a state of nociceptive sensitization caused by exposure to opioids" www.ncbi.nlm.nth.gov/pubmed/21412369. Many pain specialists are speaking out against the use of long-term opioids for common problems like lower back pain, fibromyalgia and chronic headaches. With the interrelationship of acute versus chronic pain, existing opioid medication, addiction and new opioids coming to market, education of the interrelated paradigm for healthcare professionals is more important than ever. (3) The greater the awareness of potential benefits and risks of opioid prescribing will give rise, from a clinical standpoint, to second thoughts about prescribing practices.

Chronic pain affecting tens of millions of people in the United States is associated with functional loss, disability, reduced quality of life, high healthcare costs and even premature death. Physicians are more likely to recognize and treat chronic pain than in the past with the number of prescriptions written for opioids increasing 10-fold since 1990. We must not prioritize chronic pain over addiction or addiction over chronic pain. Millions of people with chronic pain are at risk for addiction or overdose when treated with opioid medications. Many people with addiction also have chronic pain. We must recognize both will remain significant and interconnected clinically; a public health challenge for the foreseeable future. To-date, 45 state medical boards follow the Federation of State Medical Boards policies on best practices for managing chronic pain with prescription opioids." (4)

The Centers for Disease Control and Prevention have declared a national "epidemic" in regards to opiate prescription drug addiction. Over the last ten years, more than 125,000 Americans have died from opiate pain killer overdoses. It was estimated over 28 million people suffer from addiction and less than 12% received treatment in 2010 (SAMHSA, 2010 NSDUH). This is a national issue that has no urban/rural boundaries. Substance abuse is a complex problem that has societal, public health and public safety ramifications that cross all socio-economic and state boundaries.

In WV, it is estimated that the cost of substance abuse is more than 1.8 billion in 2006 and of that 407 million was in direct costs ("Governor's Comprehensive Strategic Plan to Address Substance Abuse in WV"). From three deaths related to drug overdose per 100,000 people in 1980, the number is now 13 overdose deaths per 100,000 people. For every single opiate related overdose death, the CDC says there are 15 abuse center admissions, 26 emergency room visits, 115 people abusing opiates and are dependent, 733 non-medical users of opioid pain killers and 4.35 million in related healthcare costs. Albeit impressive statistics, these are families, parents, siblings and children http://www.tauntongazette.com/artide/20140503/ NEWS/140508507. (5)

The drug of choice for our adolescents age 12-18 is often prescription drugs from family, friends and others. The 2009 national survey on drug use and health (NSDUH) reports that 23.5 million people nationwide (approximately 9.3% of the US population, age 12 and over) have used hydrocodone for non-medical purposes. In 2009, an estimated 86,258 emergency department visits were associated with non-medical use of hydrocodone, according to the Drug Abuse Warning Network (DAWN ED). This is particularly alarming knowing the prevalence of illicit use among school age children. The 2010 Monitoring the Future Survey reports that 2.7%, 7.7% and 8.0% of 8th, 10th and 12th graders, respectively, used Vicodin non-medically in the previous year. Drug overdose deaths have surpassed homicides and fatal traffic accidents representing 38,000 overdose deaths in the US in 2010 (500% increase since 1980) and have continued to increase.

Understanding the risks for developing substance use disorders and the red flags that can emerge in clinical practice is important. Clinicians need to understand, albeit unintentional, the iatrogenic introduction of opiates to the opiate naive patient at risk of addictive illness occurs; even in the treatment of acute medical conditions requiring legitimate opioid medications. Many individuals suffering addiction may have started with a prescription such as Vicodin or Lortab for pain, but progressed to stronger medication and ultimately other substances like heroin. Addiction specialists often refer to hydrocodone as a "gateway drug" leading to more potent medications, physical dependence on those medications and full blown addiction including use of other illicit substances. It is rare for a patient's pain killer addiction to start with snorting or injecting opiates. Their addiction started as result of legitimately prescribed medication taken as whole pills, as prescribed, progressing to taking more than as prescribed, snorting or injecting after their addiction progressed. In the 10 years, 1999-2007, the per capita retail purchases of methadone, hydrocodone and oxycodone in the United States increased 13-fold, 4-fold and 9-fold respectively. Hydrocodone is a drug of choice for risk adverse people, those who are unlikely to abuse more potent medications, including heroin. Oxycodone would be preferred by the younger group tending to be more risk tolerant. Hydrocodone is sometimes viewed as a "white collar" addiction.

The Top Five prescriptions causing the most overdoses in WV; methadone, oxycodone, fentanyl, hydrocodone and morphine with hydrocodone consistently being detected among the top three over the last ten years. According to the CDC, nationally unintended drug poisoning deaths increased 68% during 1999-2004 with WV leading at a rate of 550%. In 2010, WV ranked number one at 28.9 deaths per 100,000. Hydrocodone related deaths, prescribing and associated sales and treatment related admissions have been well correlated (CDC. MMWR 2011).

Hydrocodone (Vicodin, Vicodin ES. Vicodin HP. Anexsia. Lortab. Lorcet. Lorcet Plus, Norco, Zydone): Licitly, hydrocodone is an anti-tussive (cough suppressant) and narcotic analgesic for the treatment of moderate to severe pain. It is as effective as or more effective than codeine for cough suppression and nearly equipotent to morphine in the treatment of pain. 139 million prescriptions for hydrocodone containing products were dispensed in 2010 under several hundred brand names and generic products most frequently in combination with acetaminophen (Vicodin, Lortab). Hydrocodone was first reported producing euphoria and habituation in 1923. The first report of hydrocodone dependence and addiction was published in 1961.

Illicitly, hydrocodone is abused for its opiate effects often obtained through diversion. Hydrocodone abuse and diversion has escalated being the second most frequently encountered opioid pharmaceutical in drug evidence since 2009 (Drug Enforcement Administration Office of Diversion Control, Hydrocodone Update, June 2011). It is generally abused orally and often in combination with alcohol and other drugs. As with most opiates, abuse of hydrocodone is associated with tolerance, dependence and addiction. Co-formulation with acetaminophen carries the additional risk of liver toxicity when high acute doses are consumed. Liver toxicity may be less in healthy individuals who escalated their dose slowly over a long period of time.

There is a linear relationship over time with the amount of hydrocodone prescribed in grams per 100K population and frequency of hydrocodone mentions in hospital emergency department admissions. (6) CDC data indicates a similar relationship between the increased sales of opioids and unintentional overdose deaths involving opioids with a near perfect linear relationship over an eleven (11) year period, 2000-2011. (7) The volume of hydrocodone distributed over this period increases sharply. (8) In 2010, prescriptions for hydrocodone products represented two-thirds of all prescriptions for the top six opioids. (9) "Remarkably, the United States consumes almost 99 percent of all the hydrocodone in the world. In 1999, when Dr. Dougherty filed his petition asking the DEA to reschedule hydrocodone from Schedule III to Schedule II, the amount of hydrocodone used for medical purposes in the U.S. per 100k population was 4,357.03 grams. By 2011, this figure had increased 250.3 percent, to 15,263.64 grams per 100k population. Neither population growth nor a change in the prevalence or treatment of pain justifies this enormous increase." (10) As it relates to our youth, since 2002 seniors reporting past year non-medical use of hydrocodone has been 8-10% and 4-5% for oxycodone. This makes the prevalence of hydrocodone abuse second only to marijuana abuse excluding alcohol and tobacco."

Reports from NIDA also show that, as measured by emergency department records between 2004 and 2009, increases in hydrocodone abuse ranked third among pharmaceuticals and even exceeded rates noted for illicit drugs;

"The largest pharmaceutical increases [i.e., between 2004 and 2009] were observed for oxycodone products (242.2 percent increase), alprazolam (148.3 percent increase), and hydrocodone products (124.5 percent). Among ED visits involving illicit drugs, only those involving ecstasy increased more than 100 percent from 2004 to 2009(123.2 percent increase)." (12)

Hydrocodone was originally classified as a Schedule III drug, per the Controlled Substance Act (CSA) over 40 years ago. The abuse liability and potency of hydrocodone was not well understood at that time. Hydrocodone and morphine have the same potency (10 mg dose of oral hydrocodone produces the same effect as a 10 mg oral dose of oral morphine). There has been widespread agreement that the abuse liability of other Schedule II opioids and hydrocodone are the same. This similar potency to morphine, indistinguishable effects, abuse liability and being among "the most widely abused" prescription drug in the US is reflected in the recent FDA decision to reschedule hydrocodone from Schedule III to Schedule II. The FDA's drug safety and risk management advisory committee voted 19-10 in January of 2013 in favor of reclassifying hydrocodone-containing compounds from Schedule III to Schedule II drug under the Controlled Substance Act.

The DEA and FDA are working collaboratively toward implementation at this time http:// www.fda.gov/drugs/drugsafety/ ucm372089.htm. The Drug Enforcement Agency is changing its classification of hydrocodone combination drugs from "schedule III" to "schedule II," Those drugs include medicines like Vicodin or Lortab, which combine hydrocodone with acetaminophen, the main ingredient in aspirin. Patients will be limited to one 90-day supply of medication and will have to see a physician to receive a refill. The move comes more than a decade after the DEA first recommended reclassifying hydrocodone because of its risk for abuse and addiction. This single intervention of the federal government is one of the most important interventions in bringing this out of control epidemic to a more manageable level. (13)

Enter Zohydro (Zohydro[TM] ER, hydrocodone bitartrate): considered a somewhat "tainted" approval by the FDA October 25, 2013 (even after an advisory committee of independent experts voted 11-2 against approval, because of concerns about addiction). Attorney Generals from 29 states have requested the FDA reconsider its approval of Zohydro as result of public health concern over the loss of life from overdose and citing the lack of abuse-deterrent features. The FDA made it clear that Zohydro shows strong enough efficacy in reducing pain and suffering when weighed against its potential abuse liability.

A brand name, extended release analgesic formulation of pure hydrocodone manufactured by Zogenix, Inc. by Alkermes Gainesville LLC. Zohydro is a long lasting version of the pain killer hydrocodone. This recent approval of the long-acting opioid is an example of the tension of treating the challenges of chronic pain and addiction. Zohydro is in the category of extended release and long-acting oral opioids such as OxyContin (oxycodone hydrochloride), MS Contin (morphine sulfate) and Opana ER (oxymorphone hydrochloride).

From the website, "Zohydro [TM] ER is indicated for the management of pain, severe enough to require daily, around-the-clock, long-term opioid treatment for which alternative treatment options (e.g. non-opioid analgesics or immediate-release opioids) are inadequate. The dosage strengths and administration are 10, 15, 20, 30, 40 and 50 milligrams (mg) of hydrocodone bitartrate capsules and twice-daily (q12h) administration. Zohydro[TM] ER is indicated for severe pain that requires continuous, around-the-clock, opioid therapy and is not indicated for acute pain or PRN analgesia." (24) www.zogentx.com/ content/products/zohydro.htm.

This update is being provided as result of considerable concerns regarding the lack of safety measures being employed with the release of this drug. There is a "strong" black box warning for this Schedule II drug due to apprehension the drug will fill the recreational drug void left by the original version of OxyContin 80 mg. Zohydro's easily crushed capsules, containing up to 50 mg of pure hydrocodone, make it 10x more hydrocodone than a regular Vicodin, a lethal dose for a child. It contains significantly greater amounts of hydrocodone (whereas other hydrocodone products contain 5-7.5 mg) than currently available immediate release hydrocodone combination products typically combined with other analgesics, such as acetaminophen. It is manufactured as a powder placed into a capsule rather than a pill; therefore is easily opened by recreational abusers for snorting or solubilized with saline for injection. It does not have features to deter crushing and injecting. It has been well established that even modest safeguards have been shown to reduce the potential for inappropriate use. The extended released beads are easily chewed potentially releasing as much as 50 mg of hydrocodone at once, increasing the likelihood of overdose. The FDA did not require abuse deterrents prior to approval, so there is a high risk of abuse and overdoses. Zogenix is considering employing deterrents, but this would take considerable time prior to potential implementation. Zohydro contains no acetaminophen. Without dosing boundaries related to acetaminophen typically utilized to meter prescribing (potential liver toxicity), individual tolerance will be the only prescribing end point. As the medication becomes utilized all healthcare providers are encouraged to monitor for over utilization of this potentially dangerous drug. (15)

Non-opioid tolerant patients may be at increased risk of overdose, particularly fatal respiratory depression. Patient education is recommended on not combining Zohydro[TM] ER with over-the-counter products containing alcohol, alcoholic beverages and benzodiazepines. Zohydro" [TM] ER capsules must be swallowed whole and not crushed, chewed or dissolved as the contents may be rapidly released resulting in release and absorption of a potentially fatal dose. Product distribution started late in the first quarter of 2014. Please review the detailed instructions and specific warnings prior to prescribing or dispensing this controlled substance.

Addressing addiction, prescription drug diversion and substance use disorders in general takes a multifaceted approach. The issues surrounding these problems are complex and not solely attributable to any one factor. In order to make a real impact, policies and approaches must be broadly encompassing, comprehensive and persistent over time. Education of physicians regarding medications, both old and new, is a part of this approach. The WV State Medical Association supports education and policies that discourages diversion of prescription drugs and that facilitates treatment opportunities for individuals suffering substance use disorders.

The Paradigm for the "Epidemic" continues; involving proper opioid prescribing, the current and future impact of prescription drugs, pain, abuse and addiction. Clinicians have a critical role, not only in preventing the diversion of prescription drugs, but also in the treatment of pain and addiction; acutely and the long-term as with any other chronic medical illness affecting our society. Education of physicians, collaboration of: legislators, legal authorities, the clinicians and healthcare community, including organized medicine, and the public will provide the ability to impact the epidemic to the benefit of the public we serve. (16)

RELATED ARTICLE: AMA releases fact sheet to help physicians comply with new hydrocodone regs.

Medical News Inc. (9/24) reports that on Sept. 18, the American Medical Association "released a new fact sheet ... to assist physicians in complying with new federal regulations on prescribing hydrocodone and help avoid disruptions in patient care." A new "rule, effective October 6, 2014, reschedules hydrocodone combination products (HCPs) into Controlled Substance Schedule II." In a statement, AMA president Robert M. Wah, MD, said, "This new fact sheet explains how new regulatory changes impact both physicians and pharmacists, which will help ensure patients continue having access to the care they need under the new federal rule." For more information, please visit AMA Wire.

References

(1.) American Pain Society (APS)-33rd Annual Scientific Meeting. Abstract 448 presented May 2, 2013 http:nwww.medscape.com/viewa rticle/824702?nlid=56823_27038src=w nl_edit_dail&uac=43207EJ

(2.) J Pain, 2012; 10:988-996 Abstract "Where Opioid Prescribing is Highest ". Medscape. October 15, 2012.

(3.) Kolodny, A.. MD, "Zohydro: The FDA-Approved Prescription for Addiction", Huffington Post, Science, May 12, 2014. http://www.huffingtorpost.com/andrewkolodny-md/ zohydro-the-fdaapproved-p_b_4S55964.html

(4.) Olsen, Y.. MD, MPH; Sharfstein. J., MD: Chronic Pain, Addiction and Zohydro, NEJM, April 30, 2014.www.neim.org/doi/full/10.1056/ NEJMp1404181.

(5.) Taunton Dailey Gazette, Taunton, MA: "CDC statistics show opiate addiction a growing threat across country".

(6.) Sources: DEAARCOS, published 2004-2006, unpublished 2007-2011 (obtained by author via FOIA. August 2012); ED visits: DHHS. Substance Abuse and Mental Health Services Administration, DAWN, 2004-2010, "all misuse and abuse."

(7.) Paulozzi LJ, Weisler RH, Patkar AA. A national epidemic of unintentional prescription opioid overdose deaths: how physicians can help control it. J Clin Psychiatry. Apr 19 2011;72(5):58 9-592.

(8.) kenan k, Mack K, Paulozzi L. Trends in prescriptions for oxycodone and other commonly used opioids in the United States, 2000-2010. Open Medicine. 2012;6(2e41).

(9.) Number and (%) of top six opioids prescribed in 2010: Oxycodone: 48.227,000 TRx (26%); methadone: 4,559,000 TRx (2.5%); morphine/ combinations: 2,740,000 TRx (1.5%); fentanyl: 4,915,000 TRx (2.6%); hydromorphone/ combinations: 2.276,000 TRx (1.2%). By comparison, C-Ill hydrocodone products: 122,807.000 TRx (66.2%). Total TRx for all these opioids in 2010 estimated as 185,520.000-according to industry sources (www.DrugTopics.com)

(10.) See Letter, dated January 16, 2003, from DuPont, Robert L, Bensinger, Peter B., Coleman, John J. to the FDA Drug Safety and Risk Management Advisory Committee.

(11.) Volkow N. Curtailing Diversion and Abuse of Opioid Analgesics Wilhout Jeopardizing Pain Treatment. JAMA. 2011;305(13).

(12.) National Institute on Drug Abuse. OrugFacts: Drug-Related Hospital Emergency Room Visits 2011; http://www.dnjgabuse.gov/publications/ drugfacts/drug-related-hospital-emergency-room-visits. Accessed Jan 14, 2013.

(13.) See Letter, dated November 6, 2012, from Acting President Stuart Gitlow, MD, MBA, MPH, FAPA, American Association of Addiction Medicine to FDA Commissioner Margaret A. Hamburg, M.D. (available: http://www.asam. org/docs/asam-news-archives/fda-rescheduling-hydrocodone-comments.pdf).

(14.) See Newsletter, Medical Board of California. Spring 2014, Page 10.

(15.) See Pharmaceutical Alert Bulletin, US Dept. Health a Human Services Office of Inspector General--Office of Investigations.

(16.) Hall, P., MD, Hawkinberry. II, D., MD, Moyers-Scott, P.. PA-C, "Prescription Drug Abuse & Addiction: Past, Present and Future: The Paradigm for an Epidemic", WV State MedicalJournal. Special Issue. July/August 2010|Vol. 106.

P. Bradley Hall, MD, DABAM, FASAM

Dr. Hall is the Executive Medical Director of the WV Medical Professionals Health Program, President-Elect of the Federation of State Physician Health Programs, President of the WV Society of Addiction Medicine and a member of the Governor's Advisory Council on Substance Abuse.
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Title Annotation:Member Perspective
Author:Hall, P. Bradley
Publication:West Virginia Medical Journal
Date:Nov 1, 2014
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