Showing posts with label opioid addiction. Show all posts
Showing posts with label opioid addiction. Show all posts

Thursday, July 26, 2018

EBR/GZR safe/effective for people with HCV receiving opioid agonist therapy

Clin Transl Sci. 2018 Jul 24. doi: 10.1111/cts.12564. [Epub ahead of print]

No Pharmacokinetic Interactions Between Elbasvir or Grazoprevir and Methadone in Participants Receiving Maintenance Opioid Agonist Therapy
Feng HP1, Guo Z1, Caro L1, Marshall WL1,2, Liu F1, Panebianco D1, Vaddady P1, Reitmann C1, Jumes P1, Wolford D1, Fraser I1,3, Valesky R1, Martinho M1, Butterton JR1, Iwamoto M1, Webster L4,5, Yeh WW1.

Download Full Text Article
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We conducted two phase I trials to evaluate the pharmacokinetic interactions between elbasvir (EBR), grazoprevir (GZR), and methadone (MK-8742-P010 and MK-5172-P030) in non-hepatitis C virus (HCV)-infected participants on methadone maintenance therapy. Coadministration of EBR or GZR with methadone had no clinically meaningful effect on EBR, GZR, or methadone pharmacokinetics. The geometric mean ratios (GMRs) for R- and S-methadone AUC0-24 were 1.03 (90% confidence interval (CI), 0.92-1.15) and 1.09 (90% CI, 0.94-1.26) in the presence/absence of EBR; and 1.09 (90% CI, 1.02-1.17) and 1.23 (90% CI, 1.12-1.35) in the presence/absence of GZR. The GMRs for EBR and GZR AUC0-24 in participants receiving methadone relative to a healthy historical cohort not receiving methadone were 1.20 (90% CI, 0.94-1.53) and 1.03 (90% CI, 0.76-1.41), respectively. These results indicate that no dose adjustment is required for individuals with HCV infection receiving stable methadone therapy and the EBR/GZR fixed-dose regimen. PMID: 30040872 DOI: 10.1111/cts.12564

Continue to article:

Of Interest
New research: High burden of hepatitis C among people who inject drugs
(University of New South Wales) Globally, more than one in three (39 percent) people who have injected drugs in the last year are living with hepatitis C infection, according to new research from the National Drug and Alcohol Research Centre and the Kirby Institute at UNSW Sydney

Tuesday, July 17, 2018

HCV Next: Physicians Diagnosing,Treating HCV Define New Role in Opioid Crisis

Check out the July/August issue of HCV Next, just released online at Healio

Table of Contents
Cover Story 
Physicians Diagnosing,Treating HCV Define New Role in Opioid Crisis
The opioid epidemic in the United States has affected millions, exposing them to health risks that include a range of infectious diseases.

Point-of-Care HCV Assays: A Turning Point for Decentralized Diagnosis
Compared with traditional hepatitis virological tests, the benefit of point-of-care diagnostics is their use in patient care sites such as outpatient clinics, intensive care units, emergency departments and medical laboratories. Additionally, certain low- and middle-income countries have made use of point-of-care tests in blood banks.

In the Journals Plus
Most iatrogenic HCV cases unidentified until symptom onset
Insurance denials for HCV therapy increase in US

Meeting News
HCV outcomes worse for patients with public insurance, Medicaid
Homeless veterans with HCV diagnosed, treated via PCP outreach

Trend Watch

Begin here.....

On This Blog
The controversy over expensive new drugs for hepatitis C
Link to research and news articles addressing the high cost of hepatitis C drugs; insurance restrictions - private insurers/Medicaid - and availability of generic versions.

Efficacy of Generic Oral DAAs in Patients With HCV Infection
Journal of Viral Hepatitis, July 20, 2018

Sunday, July 15, 2018

New epidemic of hepatitis C, HIV, and other infections within the opioid abuse epidemic

Within opioid abuse epidemic, infectious disease epidemic emerges
Will Boggs MD

NEW YORK (Reuters Health) - There is a new epidemic of hepatitis C, HIV, and other infections within the opioid abuse epidemic, according to participants in a National Academies of Sciences, Engineering, and Medicine workshop.

There is an urgent need for actions to address this combined threat, they write in Annals of Internal Medicine,

“Opioid use disorder is like any other medical disorder, and through simple screening and starting medication treatment with the FDA-approved medications to prevent relapse to opioid use and decrease opioid craving, people can reduce acquiring infections,” Dr. Sandra A. Springer from Yale School of Medicine, New Haven, Connecticut told Reuters Health by email. “For those who do have associated infections at the time of screening, then starting treatment for their opioid use disorder can help them recover from their infectious diseases as well. Two for the price of one.”
Continue reading:
Sandra A. Springer, MD; P. Todd Korthuis, MD, MPH; Carlos del Rio, MD 
As a result of the opioid use disorder (OUD) epidemic (1), new epidemics of hepatitis C virus (HCV) and HIV infection have arisen and hospitalizations for bacteremia, endocarditis, skin and soft tissue infections, and osteomyelitis have increased (2–4). Optimal treatment of these conditions is often impeded by untreated OUD resulting in long hospital stays, frequent readmissions due to lack of adherence to antibiotic regimens or reinfection, substantial morbidity, and a heavy financial toll on the health care system. Medical settings that manage such infections offer a potential means of engaging people in treatment of OUD; however, few providers and hospitals treating such infections have the needed resources and capabilities (5). There is thus an urgent need to implement and scale up effective OUD treatment in health care settings to address the intersecting epidemics of OUD and its infectious disease (ID) consequences (6). The American College of Physicians (7), the Infectious Diseases Society of America (8), and the National Institutes of Health (9) have issued calls for action. Providers who treat the infectious complications of OUD, including ID physicians, hospitalists, emergency medicine physicians, intensivists, surgeons, obstetrician-gynecologists, pediatricians, nurses, advanced practice registered nurses, and physician assistants are at the forefront of these epidemics and are well-positioned to integrate OUD treatment in the context of ID management.

Tuesday, June 19, 2018

Methadone and buprenorphine reduce risk of death after opioid overdose

Methadone and buprenorphine reduce risk of death after opioid overdose
NIH research confirms effective treatments for opioid use disorder are underutilized.

A National Institutes of Health-funded study found that treatment of opioid use disorder with either methadone or buprenorphine following a nonfatal opioid overdose is associated with significant reductions in opioid related mortality. The research, published today (link is external) in the Annals of Internal Medicine, was co-funded by the National Institute on Drug Abuse (NIDA) and the National Center for Advancing Translational Sciences, both parts of NIH.

Study authors analyzed data from 17,568 adults in Massachusetts who survived an opioid overdose between 2012 and 2014. Compared to those not receiving medication assisted treatment, opioid overdose deaths decreased by 59 percent for those receiving methadone and 38 percent for those receiving buprenorphine over the 12 month follow-up period. The authors were unable to draw conclusions about the impact of naltrexone due to small sample size, noting that further work is needed with larger samples. Buprenorphine, methadone, and naltrexone are three FDA-approved medications used to treat opioid use disorder (OUD).

The study, the first to look at the association between using medication to treat OUD and mortality among patients experiencing a nonfatal opioid overdose, confirms previous research on the role methadone and buprenorphine can play to effectively treat OUD and prevent future deaths from overdose.

Despite compelling evidence that medication assisted treatment can help many people recover from opioid addiction, these proven medications remain greatly underutilized. The study also found that in the first year following an overdose, less than one third of patients were provided any medication for OUD, including methadone (11 percent); buprenorphine (17 percent); and naltrexone (6 percent), with 5 percent receiving more than one medication.

In an editorial commenting on the study, Dr. Nora Volkow, director of NIDA, said, “A great part of the tragedy of this opioid crisis is that, unlike in previous such crises America has seen, we now possess effective treatment strategies that could address it and save many lives, yet tens of thousands of people die each year because they have not received these treatments. Ending the crisis will require changing policies to make these medications more accessible and educating primary care and emergency providers, among others, that opioid addiction is a medical illness that must be treated aggressively with the effective tools that are available.” The editorial was co-authored by NIDA scientist Dr. Eric Wargo.

Another alarming study finding was that despite having had an opioid overdose, 34 percent of people who experienced an overdose were subsequently prescribed one or more prescriptions for opioid painkillers over the next 12 months, and 26 percent were prescribed benzodiazepines.

“Nonfatal opioid overdose is a missed opportunity to engage individuals at high risk of death,” said Marc Larochelle, M.D., the study’s lead investigator at Boston Medical Center’s Grayken Center for Addiction and Boston University School of Medicine. “We need to better understand barriers to treatment access and implement policy and practice reforms to improve both engagement and retention in effective treatment.”

The authors conclude that a nonfatal opioid overdose treated in the emergency department is a critical time to identify people with OUD, and an opportunity to offer patients access to treatment inventions, providing linkage to care following their discharge, and making improvements in treatment retention.

Wednesday, June 13, 2018

Scotland’s reduction in new HCV infections due to harm reduction, not treatment

Keith Alcorn 
Published: 12 June 2018

The reduction in new hepatitis C virus (HCV) infections that has taken place in Scotland since 2008 is most likely due to increased provision of needle and syringe programmes and opioid substitution therapy, rather than a reduction in the number of people with hepatitis C as a result of increased treatment of HCV infection, a modelling study published in the journal Addiction reports.

Wednesday, June 6, 2018

FDA takes action against 53 websites marketing unapproved opioids

FDA News Release
FDA takes action against 53 websites marketing unapproved opioids as part of a comprehensive effort to target illegal online sales

The U.S. Food and Drug Administration today announced that it has warned nine online networks, operating a total of 53 websites, that they must stop illegally marketing potentially dangerous, unapproved and misbranded versions of opioid medications, including tramadol and oxycodone.
Companies who fail to correct the violations, as outlined in the warning letters, may be subject to enforcement action, including product seizure or injunction.

"The FDA is taking additional steps to protect U.S. consumers from illicit opioids by targeting the websites that illegally market them and other illicit drugs. The internet is virtually awash in illegal narcotics and we’re going to be taking new steps to work with legitimate internet firms to voluntarily crack down on these sales. As part of that effort, we’re hosting a summit with internet stakeholders to find new ways to work collaboratively with them to address these issues. At the same time, we’ll be taking action against firms whose websites deliberately break the law," said FDA Commissioner Scott Gottlieb, M.D. "This illegal online marketing of unapproved opioids is contributing to the nation’s opioid crisis. Today’s warning letters go right to the source of this illegal activity to let online network operators know that marketing illegal and unapproved opioids directly to U.S. consumers will not go unchallenged by the FDA. Opioids bought online may be counterfeit and could contain other dangerous substances. Consumers who use these products take significant risk with their lives. The new warning letters are part of a comprehensive campaign to target illegal sales of unapproved opioids. We’ll be following these actions with additional steps in coming months to crack down on the flow of illegal, unapproved opioids sold online and shipped through the mail."

Patients who buy prescription medicines from illegal online pharmacies may be putting their health at risk because the products, while being marketed as authentic, may be counterfeit, contaminated, expired, or otherwise unsafe. As noted in the warning letters, these websites offer for sale opioids that are misbranded and unapproved new drugs, including unapproved tramadol and oxycodone, in violation of the Federal Food, Drug, and Cosmetic Act.

This is particularly concerning considering that FDA-approved tramadol and oxycodone carry boxed warnings, which is the FDA’s most prominent warning, indicating that the drugs carry a significant risk of serious or even life-threatening adverse effects. The boxed warnings address risks including addiction, abuse, misuse, life-threatening respiratory depression (breathing problems) and neonatal opioid withdrawal syndrome (withdrawal symptoms in newborn babies). In addition, when taken with other central nervous system depressants, including alcohol, their use may result in coma or death.

The networks receiving warning letters include:
Instabill ECS-Rx
One Stop Pharma

"The public needs to know that no one is authorized to sell or distribute opioids via the internet in the U.S., with or without a prescription," said Donald D. Ashley, director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research. "Drug dealers and rogue website operators are using the internet to fuel the opioid crisis, heartlessly targeting millions of Americans struggling with opioid use disorder. We will continue to aggressively pursue these criminals and take swift action to protect the American public."

The FDA requested responses from each of the companies within 10 working days. The companies are directed to inform the agency of the specific actions taken to address the agency’s concerns.

Opioid addiction is an immense public health crisis. Addressing it is one of the FDA’s highest priorities and supports the U.S. Department of Health and Human Services’ 5-Point Strategy To Combat the Opioid Crisis. One critical step to addressing this public health emergency is the adoption of a more proactive approach by internet stakeholders to crack down on internet traffic in illicit drugs. Illegal online pharmacies, drug dealers and others are increasingly using the internet to further their illicit distribution of opioids, where their risk of detection and repercussions is significantly reduced.

As part of this effort, Commissioner Gottlieb has invited internet stakeholders and thought-leaders, government entities, academic researchers and advocacy groups to an Online Opioid Summit on June 27 to discuss ways to collaboratively take stronger action in combatting the opioid crisis by reducing the availability of illicit opioids online. Topics to be addressed during the Summit include: research into the ease with which illicit opioids can be purchased online and industry approaches to addressing opioids marketed online, followed by a roundtable discussion to identify gaps and new solutions.

In addition to health risks, illegal online pharmacies can pose other risks to consumers, including credit card fraud, identity theft, and computer viruses. The FDA encourages consumers to report suspected criminal activity to the FDA’s Office of Criminal Investigation. The FDA also provides consumers with information to identify an illegal online pharmacy and information on how to buy medicine safely online through BeSafeRx: Know Your Online Pharmacy.

The FDA remains committed to addressing the national crisis of opioid addiction on all fronts, with a significant focus on decreasing exposure to opioids and preventing new addiction; supporting the treatment of those with opioid use disorder; fostering the development of novel pain treatment therapies and opioids more resistant to abuse and misuse; and taking action against those who contribute to the illegal importation and sale of opioids. The agency will also continue to evaluate how opioids currently on the market are used, in both medical and illicit settings, and take regulatory action where needed.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Tuesday, May 15, 2018

Are pharmaceutical marketing payments to physicians for opioids associated with prescribing?

Are Pharmaceutical Marketing Payments to Physicians for Opioids Associated With Prescribing?

Bottom Line: Pharmaceutical industry marketing of opioid products to physicians through nonresearch payments, which can include speaking fees and meals, was associated with greater opioid prescribing.

Why The Research Is Interesting:
Many opioid-related overdose deaths involve prescription opioids, and prescription opioids can commonly be a person’s first encounter on a path to illicit use. Marketing by the pharmaceutical industry to physicians is widespread but marketing of opioids and its influence on prescribing is unclear.

What (Study Methods): Linking of two U.S databases to identify all nonresearch payments from the pharmaceutical industry to physicians marketing opioid products (excluding buprenorphine hydrochloride marketed for addiction treatment) and to gather information on all claims from physicians who wrote opioid prescriptions (initial or refill) filled for Medicare beneficiaries in 2015

Study Limitations: Possibility of reverse causation because physicians who receive industry payments may be inclined to prescribe opioids; study establishes association, not cause and effect
Amidst national efforts to curb the overprescribing of opioids, our findings suggest that manufacturers should consider a voluntary decrease or complete cessation of marketing to physicians. Federal and state governments should also consider legal limits on the number and amount of payments.

Research Letter
JAMA Intern Med. Published online May 14, 2018.
Association of Pharmaceutical Industry Marketing of Opioid Products to Physicians With Subsequent Opioid Prescribing
Scott E. Hadland, MD, MPH, MS1,2,3; Magdalena Cerdá, DrPH, MPH4; Yu Li, MD, PhD5; et al Maxwell S. Krieger, BS5; Brandon D. L. Marshall, PhD5

Despite the increasing contribution of heroin and illicitly manufactured fentanyl to opioid-related overdose deaths in the United States, 40% of deaths involve prescription opioids.1 Prescription opioids are commonly the first opioid encountered in a trajectory toward illicit consumption.2 Although opioid prescribing has declined nationally, rates in 2015 were triple those in 1999 and remain elevated in regions of the country with higher numbers of overdoses.3

Pharmaceutical industry marketing to physicians is widespread, but it is unclear whether marketing of opioids influences prescribing.4 We studied the extent to which pharmaceutical industry marketing of opioid products to physicians during 2014 was associated with opioid prescribing during 2015.
Continue reading:

Related Material: Two other studies, “Weekly and Monthly Subcutaneous Buprenorphine Depot Formulations vs. Daily Sublingual Buprenorphine with Naloxone for Treatment of Opioid Use Disorder: A Randomized Clinical Trial,” and “Association of an Opioid Standard of Practice Intervention with Intravenous Opioid Exposure in Hospitalized Patients,” also are available on the For The Media website.

For more details and to read the full study, please visit the For The Media website.
Editor’s Note: The article contains funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Monday, May 7, 2018

Opioids and Infectious Disease

Opioids and Infectious Disease
By Gabriella Fiorino | May 7, 2018

The current opioid epidemic is a serious health concern. It impacts the mentally ill and sexually abused, and the men and women selflessly serving the country. Now, findings by the Health Resources & Service Administration link the epidemic to outbreaks of infectious diseases, significantly impacting numerous communities.

Towns across America have experienced at least 500% increases in instances of Hepatitis C, with 75% of new cases associated with intravenous painkiller use. There have also been surges in syphilis, chlamydia, gonorrhea, and other illnesses.

Many physicians believe the culprit of the epidemic to be the overprescribing of opiates. Indeed, last year the country witnessed the most massive health care fraud crackdown in U.S. history, as reported by Liberty Nation. Health care providers were caught distributing medically unnecessary narcotics to patients for financial gain.

Despite the aggressive investigations continuously underway by the Justice Department, two million citizens presently suffer from prescription opioid addiction. Also, more than twelve million Americans misused these medications within the past two years.

Reversing An Overdose Isn't Complicated, But Getting The Antidote Can Be

Of Interest
Should you carry the opioid overdose rescue drug naloxone?
Posted May 04, 2018, 6:30 am , Updated May 07, 2018, 11:57 am
Scott Weiner, MD
I would answer “yes” but with some qualifiers. As the Surgeon General wrote, naloxone is most effective for people taking high doses of opioids, who are misusing prescription opioids, or who are using illicit opioids. It makes sense to have naloxone on hand if you fall into one of these categories, or if you are a friend, family member, or community member who comes into contact with people at risk for overdose. You should also know that in most states, you can request naloxone at most pharmacies without a prescription.

Reversing An Overdose Isn't Complicated, But Getting The Antidote Can Be
May 7, 20185:01 AM ET
Jake Harper

Heard on Morning Edition
A few months ago, Kourtnaye Sturgeon helped save someone's life. She was driving in downtown Indianapolis when she saw people gathered around a car on the side of the road. Sturgeon pulled over and a man told her there was nothing she could do: Two men had overdosed on opioids and appeared to be dead.

"I kind of recall saying, 'No man, I've got Narcan,' " she says, referring to the brand- name version of the opioid overdose antidote, naloxone. "Which sounds so silly, but I'm pretty sure that's what came out."

Sturgeon sprayed a dose of the drug up the driver's nose, and waited for it to take effect. About a minute later, she says, the paramedics showed up.

View Article:

Monday, April 30, 2018

Battling an Epidemic - Part Three: What Iowa's parents, doctors and others are doing to overcome opioids' fatal effects

Battling an Epidemic - Part Three: What Iowa's parents, doctors and others are doing to overcome opioids' fatal effects
Michaela Ramm and Lee Hermiston, The Gazette April 30, 2018 | 9:43 am

Its staff and volunteers work in Cedar Rapids, Iowa City and Des Moines to address the impacts of the national opioid crisis that has caused the death of more individuals in 2016 than the number of Americans who were killed during the Vietnam War, according to the Police Executive Research Forum.

And they are not alone. The organization is among several others across the state — including public agencies, law enforcement, private insurance company officials and elected state leaders — working toward the same goal to address the effects of the opioid crisis within the state’s borders.

Iowa Harm Reduction Coalition Founder Sarah Ziegenhorn said the nonprofit operates under the assumption substance abuse and addiction cannot be totally eradicated in the population, so the main priority is to prevent the spread of disease and infection associated with injectable drug use, such as HIV or hepatitis C....

Friday, April 27, 2018

Opioid epidemic: More funding needed

In The Journals 
Increases in Acute HCV Infection, Injection Drug Use, and the Opioid Epidemic
April 27, 2018
It appears that the increase in acute hepatitis C virus (HCV) infection in the United States is related to the country's opioid epidemic and increase in injection drug use, according to a study in the American Journal of Public Health.

Published: 25 April 2018
For over a decade, the vast majority of new hepatitis C virus (HCV) infections have been among young people who inject drugs (PWID). Well-characterized gaps in chronic HCV diagnosis, evaluation, and treatment have resulted in fewer than 5% of PWID receiving HCV treatment. While interferon-based treatment may have intentionally been foregone during part of this time in anticipation of improved oral therapies, the overall pattern points to deficiencies and treatment exclusions in the health care system. Treatment for HCV with all-oral, highly effective direct-acting antiviral medication for 12 weeks or less is now the standard of care, putting renewed focus on effective delivery of care. We describe here both the need for and process of chronic HCV care under the roof of addiction medicine.

Opioid epidemic: More funding needed
Nardy Baeza Bickel

ANN ARBOR—More funding is needed to address the opioid epidemic that is projected to cost the U.S. economy $200 billion by 2020, says a University of Michigan researcher.

In an article published in JAMA Psychiatry, Rebecca Haffajee, assistant professor of health management and policy at the U-M School of Public Health, says funding has been insufficient to face the epidemic that in 2016 took the lives of 116 people per day.

"Recent estimates have suggested that the crisis is costing the country tens of billions, perhaps hundreds of billions, per year, but our allocations are not catching up to those costs," Haffajee said. "Congress is starting to have an appreciation of the magnitude of the epidemic and what it's going to cost to really get us over this, but we're not nearly there yet.

"We're hearing from the states that they are overwhelmed. They do not have the resources to actually address this crisis, and they need the federal government to lend resources to help them address it."

Haffajee and co-author Richard Frank of the Department of Health Care Policy at Harvard Medical School propose focusing on four areas to deal with the acute, emergency aspects of the opioid crisis. They say that putting federal funding—on the order of hundreds of millions—into specific programs could help save lives and mitigate other immediate harms in the short-term.

The researchers suggest:
Congressional appropriation of money into an emergency fund to purchase naloxone hydrochloride, a drug that when used correctly and promptly can reverse opioid overdose.
Provision of funds for clean syringe programs that facilitate substance use treatment and access to naloxone, and could also help reduce transmission of infectious diseases such as HIV and Hepatitis C. Outbreaks of these diseases have been linked to the opioid epidemic.
Increased funding for state foster care systems. Opioid-related overdoses have been blamed for a recent peak in the number of children in foster care—a 7-percent increase between 2012 and 2016.
Provision of funds and relaxed regulations to help deal with severe shortages of medication-assisted therapy in rural communities.

Haffajee and Frank say that opioid-related overdose deaths increased 80 percent between 2012 and 2016. Synthetic opioid-related overdose deaths, in particular, have skyrocketed—a 675-percent increase during that time.

"That's just an astronomical increase and actually shows no signs of slowing down," Haffajee said. "We propose that the most direct mean of averting these deaths is to expand access to and training on administering naloxone hydrochloride, a drug that when used correctly and promptly can reverse opioid overdose. But the deaths are just the tip of the iceberg.

"For every death, you have multiple hospitalizations and emergency department visits and other adverse health outcomes that precede or surround death."

Haffajee said there is good evidence that medication-assisted treatment can improve outcomes for those with opioid use disorders, especially those in rural communities.

"We know that the provider shortages are very acute in rural areas, with over 90 percent of rural counties lacking an opioid treatment program and 70 percent lacking a buprenorphine provider," she said. "So there are a lot of counties where people would not even be able to actually access this treatment. And we know that the rates of overdoses and the increases in those places are particularly high as well."

Haffajee said it's important to know that these measures would provide temporary emergency relief, but a long-term plan is needed as well.

"There is some misconception that we're going to be able to cure the addiction suddenly and immediately and that's not what the clinical evidence tells us," she said. "We should be thinking about it as a chronic health condition much like diabetes.

"Many people will need to be treated for years, not just for a short amount of time or a couple of months. But we need people to get started on treatment and then continue to provide support."

More information:
Article in JAMA Psychiatry: Making the Opioid Public Health Emergency Effective
Rebecca Haffajee

Thursday, April 26, 2018

Strategies for Reducing Opioid-Overdose Deaths — Lessons from Canada

April 26, 2018
N Engl J Med 2018; 378:1565-1567
DOI: 10.1056/NEJMp1800216

Strategies for Reducing Opioid-Overdose Deaths — Lessons from Canada
Evan Wood, M.D., Ph.D.

Audio Interview with Dr. Evan Wood on actions taken by Canada to reduce opioid-overdose deaths.
Listen Here.....

As the United States faces this unprecedented epidemic, there are lessons to be learned from Canada, which has taken bold action on a number of fronts with the aim of reducing deaths related to fentanyl, fentanyl analogues, and other opioids. For instance, in March 2016, the Canadian government made the overdose-reversal drug naloxone available without a prescription. Although naloxone is also increasingly available in many regions of the United States, laws in 14 states provide no immunity from criminal prosecution for health care providers who prescribe or distribute it to laypersons. Furthermore, in 36 states, existing laws make possession of naloxone without a prescription illegal.

The Canadian government has also passed legislation aimed at facilitating the development of medically supervised injection facilities, where people who use drugs can inject opioids they buy on the street under the supervision of health care staff. Although research has found that supervised injection facilities can reduce rates of fatal overdoses by more than 30% in communities with high rates of drug use1 and can help facilitate greater uptake of addiction treatment, there are few, if any, such programs in the United States. In recent months, however, public health officials in several U.S. cities, including San Francisco, Seattle, and Philadelphia, have endorsed plans to open pilot supervised injection programs to address increasing rates of overdose deaths.

Tuesday, April 10, 2018

Blog Updates: Pill testing as harm reduction, Vitamin B12 and Your Liver & International Liver Congress

International Liver Congress 2018 
The meeting will begin tomorrow! On Wednesday the "EASL Recommendations on Treatment of Hepatitis C 2018" will be released.

Just Updated April 11 - EASL Recommendations on Treatment of Hepatitis C 2018
Read the latest EASL clinical guideline publications in Journal of Hepatology, start by viewing EASL Recommendations on Treatment of Hepatitis C 2018 shared by @HenryEChang via Twitter, review all guideline links, here.....

Of Interest
Download The App - EASL HCV Advisor
The HCV Advisor is available in two editions. The EASL HCV Advisor will give recommendations based on EASL Recommendations for Treatment of Hepatitis C. The Swiss HCV Advisor will give recommendations specifically for Switzerland. Learn more here.....

Updated Today
Check out news from the conference with a list of websites (still in the process of being updated) offering coverage, meeting highlights, learning activities, with interviews and a summary of the meeting. This page will stay current as information is made available, watch the sidebar for updates.

New Online
MedPage Today
April 10, 2018
Clinical practice guidelines to include HCV tx recommendations, alcoholic liver disease

Hepatitis C: What Stands in the Way of Elimination?
The World Health Organization set a goal of eliminating viral hepatitis by 2030. What are the barriers to achieving this for hepatitis C? Four experts weigh in.

Yun Lu, Xiuze Jin, Cheng-a-xin Duan, Feng Chang
DCV+ASV is not only an effective and well-tolerated regimen to treat chronic HCV genotype 1b infection treatment-naïve patients, but also is more cost-effective than PR regimen. DCV+ASV can benefit both the public health and reimbursement system in China.

On Twitter From @HenryEChang 
What are the research gaps when evaluating progress towards viral hepatitis elimination?
In this @jiasociety commentary, Drs. Anders Boyd, Léa Duchesne & @karlacombe highlight some recent advances & offer important perspectives.

In The Media
Hepatitis C: A novel point-of-care assay
April 10, 2018
One of the major challenges identified by the WHO in efforts to eradicate the hepatitis C virus is the diagnosis of chronic cases that are generally asymptomatic. Major progress is required for new diagnostic techniques that can be 'decentralized,' in other words accessed by populations and countries with limited resources. Scientists have now developed and validated a rapid, reliable, point-of-care HCV assay.

In Your 60s: Blood Pressure, Hepatitis C, Cancer Risk
April 10, 2018
In your 60s you are likely to have a long, healthy life ahead of you. Men turning 65 this year can expect to live, on average, to age 84.3; women, until age 86.6.

End-of-Treatment HBsAg Levels May Predict HBV Relapse in Chronic Hepatitis B
April 10, 2018
End-of-treatment HBsAg levels may be a clinically useful biomarker to predict HBV relapse in patients with chronic hepatitis B regardless of HBeAg status.

BMC Blog Network
Pill testing as harm reduction – a return to pragmatism in Australian drug policy
April 10, 2018
Pill testing involves party and festival-goers having a sample of their drugs tested on-site by scientists, who can then provide information to the user about what they are taking so they can make a more informed decision.

Pacific Hepatitis C Network (PHCN)
Hep C Resources in BC Project - Read the report "here."
The team at PHCN is happy to report that our Hep C in BC Resources project has recently drawn to a close. This project ran from last fall to the end of March. We are excited to share the full report of this project (as well as a summary version) "here."

Treatment Update
CATIE’s flagship digest on cutting-edge developments in HIV and hepatitis C research and treatment.

Read today's news or a nice summary of notable headlines published in the latest issue of The Weekly Bull.

Treatment Action Group
TAGline Spring 2018


World Hepatitis Alliance

Blog Updates
HEP Blogs
April 9, 2018
The high cost of hepatitis C treatment and lack of access to affordable health care are major obstacles to large scale and evenly distributed treatment. A recent study found that almost half of Medicaid patients were refused hepatitis C treatment. Moreover, there is a major inadequacy when it comes to screening people for viral hepatitis.

April 4, 2018
When you’ve been diagnosed with Hepatitis C or another liver condition it’s hard not to worry. Our thoughts naturally drift to thousands of questions and what ifs. Can you relate?

April 5, 2018
I wish someone really knew the truth about how vitamins affected our liver. Do you ever just want an honest truthful answer? I’ve researched a lot, and can say, that for myself..

April 9, 2018
Many with hepatitis C, including many who have been cured, live with chronic pain and seek out ways to manage it. While doctors may prescribe pain medications, not everyone wants to take

How Did You Contract It?
April 9, 2018
Answering the most asked question given to those diagnosed with hep C: “How did you contract it?” The uncomfortable qustion This has got to be the most uncomfortable question anyone fighting hepatitis..

Going Through Rough Relationships After Diagnosis
March 30, 2018
Many with hepatitis C experience rough relationships after diagnosis. For myself, I went through a horrible divorce that really left me feeling alone, afraid, unattractive, and frankly sick. (All while in the middle of fighting for my life.) It was not that I blame hep C for this relationship ending but it contributed greatly to the dismay.

I Help C
April 4, 2018
I could look you straight in the eye, and yet not be aware of what I was doing. The world inside my head that didn’t always follow reality. Getting drunk produces the same results, but I wasn’t drunk. So does mental illness, but I wasn’t mentally ill. I had hepatic encephalopathy, or HE. Let’s talk about hepatic encephalopathy causes treatments symptoms.

Creating a World Free of Hepatitis C
Donate Life: Organ Donation and Transplantation
on April 5, 2018
It’s National Donate Life Month, and a time to increase awareness about organ and tissue donation. I am using this opportunity to implore readers to be organ donors.

Approximately 5-10% of people do not develop protective antibodies following the completion of the hepatitis B vaccine series. This is confirmed with a blood test called an anti-HBs titer test which is given 4 weeks following the completion of the series. If the test shows the titer is less then 10 mIU/mL the general recommendation is to complete the series again using a different brand of vaccine (e.g. if you received Engerix B, the first time, switch to Recombivax the 2nd time or vice-versa). A person is considered to be a “non-responder” if they have completed 2 full vaccination series’ without producing adequate protective antibodies.

On Twitter
It's time to get ready for Viral Hepatitis Awareness Month in May! Check out all the resources that @cdchep has to celebrate!

CDC Hepatitis - Save The Date: Mon, Apr 16, 2018 2:00 PM - 3:30 PM EDT
Preparing for Hepatitis Awareness Month? Join us 4/16 at 2pm for a webinar with @NASTAD and @HepBUnited to learn about available resources and get event ideas!
Register here:

Harm Reduction Coalition

Amplifying Hope
Interviewing the Unsung Champions of Harm Reduction
Over the next few months we will be interviewing a number of influential harm reduction and drug policy reform advocates from across the country. These are the people who are working against incredible odds, are largely unrecognized and serve as inspiration to the wider harm reduction community. Our aim is to amplify hope by telling their stories, uplift the people and programs delivering harm reduction services, and raise awareness about the strength and resilience of the harm reduction community across the U.S.

HIV and ID Observations
Latest DHHS Guidelines for Initial HIV Therapy Now Include 5 Choices — But Really 2 Are Best
April 8, 2018
On March 28, the Department of Health and Human Services Guidelines issued an update to the HIV treatment guidelines, with a focus on the recent approval of bictegravir/TAF/FTC...

Al D. Rodriguez Liver Foundation
Lifestyle Mindfulness for Your Liver
April 3, 2018
Healthy lifestyle remains the best defense against non-alcoholic liver disease
Do you know that you or a loved one may suffer from non-alcoholic fatty liver disease (NAFLD)? You may not have heard of such disease — but NAFLD has become the most common cause of chronic liver disease in the United States, slowly making its way as the next global epidemic.

Harvard Health Blog
A study comparing a low-fat diet and a low-carb diet found that weight loss for both groups were quite similar, and both led to significant health improvements for the participants. Diet for weight loss was part of a broader strategy of lifestyle change for both groups as well.

In Case You Missed It 

Health News Review
April 10, 2018

Physician payments linked to scripts for cancer drugs from Novartis, Pfizer and more: study
April 10, 2018
Many lawmakers worry that when pharma companies pay physicians—for speaking engagements, say, or hotel rooms at conferences—those on the receiving end are more likely to prescribe products from drugmakers that dole out the money. That concern even sparked a provision in the Affordable Care Act that requires drug and device companies to disclose any physician payment greater than $10.

A checkup for the flu vaccine
April 10, 2018
Influenza causes almost 650,000 deaths worldwide each year, yet a long-lasting, protective vaccine remains elusive. Global investment—both scientific and financial—in a universal flu vaccine is overdue. In this month's editorial, we call for a sustained commitment and global investments towards a universal flu vaccine.

Single Quadrivalent Flu Shot in IBD Patients
Reuters Health Information April 9, 2018

Informational Links
Hepatitis C (HCV) Medications Blog
HCV Advocate’s Hepatitis C (HCV) Medications blog.
The intent of this blog is to keep our website audience up-to-date on information about hepatitis meds. People are encouraged to submit questions and post comments.

Until next time,

Friday, April 6, 2018

Listen: How to administer naloxone (Narcan) & How it can save a life of someone who overdoses on opioids

How naloxone can save life of someone who overdoses on opioids
March 30th, 2018

Listen here:

Naloxone, a medication that can reverse the effects of an opioid overdose, can be purchased over the counter from pharmacies in New York and several other states, says Willie Eggleston, a clinical toxicologist and doctor of pharmacy from the Upstate New York Poison Center. He explains how to administer naloxone, which is sold under the brand name Narcan, and how the medication works. He also tells about the Good Samaritan Law designed to protect people who are trying to help.

For more detailed information about naloxone, visit the New York State Department of Health website or this video (including demonstrations on how to administer naloxone, which starts at 44:37), from the SUNY University at Buffalo College of Pharmacy.

National Institute on Drug Abuse
April 5, 2018
Opioid Overdose Reversal with Naloxone (Narcan, Evzio) | National Institute on Drug Abuse (NIDA)

April 5, 2018
Surgeon General Urges More Americans To Carry Opioid Antidote
As opioid-related deaths have continued to climb, naloxone, a drug that can reverse overdoses, has become an important part of the public health response.

April 4, 2018
Nuala Sawyer
San Francisco has one of the lowest fatal-overdose rates in the U.S. Here's why.

March 30, 2018
If you or a loved one wants to beat an opioid addiction, first make sure you have a handy supply of naloxone, a medication that can reverse an overdose and save your life.

New England Journal of Medicine
March 29, 2018
Listen: Interview with Dr. Jake Liang on the increasing spread of hepatitis C virus associated with injection-drug use.

Hepatitis C in Injection-Drug Users — A Hidden Danger of the Opioid Epidemic
T. Jake Liang, M.D., and John W. Ward, M.D.
Much has been written about the escalating crisis of opioid-overdose deaths in the United States and its mounting social and economic costs. Although political and public health leaders have begun to confront this urgent problem, hidden beneath it lies another danger: the increasing spread of hepatitis C virus (HCV) associated with injection-opioid use
Related article

Supervised Injection Sites Gain Ground in U.S.

Supervised Injection Sites Gain Ground in U.S.
by Liz Highleyman
Contributing Writer, MedPage Today
Evidence they can reduce overdose deaths and HIV and viral hepatitis transmission

Several cities are vying to become the first to open sanctioned supervised injection facilities in the United States in an effort to reduce overdose deaths, infectious disease transmission, and other drug-related harms.

Supervised injection services remain controversial, with some opponents fearing such facilities will encourage drug use and attract more drug users to an area -- the same arguments made against syringe exchange programs, which are now a widely accepted public health intervention. But opposition to supervised injection sites appears to be waning in the face of a growing overdose crisis and concern about visible public drug use.

San Francisco appears to be on track to open the first such sites this summer, but New York City, Baltimore, Boston, Denver, Philadelphia, and Seattle are also in the running. In addition, legislative efforts to allow supervised injection facilities are underway in several states.

Thursday, April 5, 2018

Surgeon General Urges More Americans To Carry Opioid Antidote

Surgeon General Urges More Americans To Carry Opioid Antidote
April 5, 201812:01 AM ET

Heard on Morning Edition 
As opioid-related deaths have continued to climb, naloxone, a drug that can reverse overdoses, has become an important part of the public health response.

When people overdosing struggle to breathe, naloxone can restore normal breathing and save their lives. But the drug has to be given quickly.

On Thursday, U.S. Surgeon General Jerome Adams issued an advisory that encouraged more people to routinely carry naloxone.

Europe's silent opioid epidemic

Europe's silent opioid epidemic
by Gary Finnegan

As opiate addiction continues to grip the United States – killing more than 100 people per day in 2016 – researchers are trying to get a handle on the scale of the problem in Europe.

The US is grappling with a major crisis driven by dependency on opioid painkillers such as fentanyl. These highly addictive prescription drugs are chemical cousins of heroin, morphine and methadone.

Strong opiates are tightly controlled in Europe but several EU countries allow over-the-counter sales of a milder pain medication: codeine. While less dangerous than heroin or fentanyl, codeine is turned into morphine in the liver and can still be toxic in high doses.

‘It’s a hidden addiction,’ said Dr Michael Bergin of Waterford Institute of Technology, Ireland. ‘Codeine abuse affects people with diverse profiles, from children to older people across all social classes.’

Some are children who got hooked on cough medicine that contains codeine – although these products are not recommend for children. Others are heroin and morphine addicts who use codeine as an occasional substitute for harder opiates.

‘But we have also identified middle-aged respectable women who became addicted to codeine having used it for pain relief or, in some cases, anxiety,’ Dr Bergin explained.

Globally, demand for codeine is high and rising – up by approximately 27% over the last decade, although precise data on codeine use is hard to come by. Information on sales is deemed by companies to be commercially sensitive and, as the painkiller is often paid for directly by consumers rather than reimbursed by a medicines payment scheme, there is no central database tracking how many people are using it, nor how much they are buying.

One project, CODEMISUSED, set out to understand how widespread codeine abuse is by interviewing users, pharmacists and doctors. It found that access to the drug varies widely across Europe, with pharmacists in some countries requiring a doctor’s prescription before they can dispense it.

'Codeine addicts speak about what they call pharmacy hopping or pharmacy tourism.'
Dr Michael Bergin, Waterford Institute of Technology, Ireland

In other jurisdictions, codeine is sold on demand. Several countries allow over-the-counter sales but apply limits to how much can be purchased and provide pharmacists with guidelines on how to limit abuse. Online sales have also grown strongly, according to researchers, with patients obtaining the drug without needing to engage with health professionals at all.

An online survey of 450 codeine users found high levels of craving among regular users. The research, conducted by King’s College London, UK, and Waterford Institute of Technology, found 20% of respondents were dependent on codeine.

‘My helper’
In-depth interviews by the Waterford-based research team found codeine addicts sometimes combine the drug with alcohol and other drugs. Users said they turn to over-the-counter codeine at the first sign of pain, anxiety or stress, some referring to it as ‘my helper’ and ‘companion’. However, several interviewees were surprised to learn that a relatively accessible product was addictive and a member of the opiate family.

For community pharmacists, codeine abuse is a real challenge. The drug has legitimate uses, making it difficult to refuse a customer who may be taking codeine appropriately. ‘Codeine addicts speak about what they call pharmacy hopping or pharmacy tourism,’ said Dr Bergin. ‘They would go from one pharmacy to another, sometimes buying 40 or 50 boxes in a single day.’

Dr Pádraig McGuinness, superintendent pharmacist of the CARA Pharmacy group, who worked with CODEMISUSED, said a brief intervention – warning the patient of the risks of opiate addiction – can be more effective than flatly refusing to sell it. ‘The customer may simply go down the street or to a different town with a different story,’ he said.

One solution examined by the project could be to implement an online tracking system similar to one introduced in South Africa, which allows pharmacists to share data on codeine purchasers and cap sales to any individual at 4 grams per month.

CODEMISUSED, which finished last year, published an extensive review of best practices and innovative approaches to balancing access to codeine with reducing the risk of addiction. These include manufacturing formulations of codeine that are less easily converted to the stronger opioid injectable deso-morphine, public information campaigns, tighter surveillance of codeine sales, training for pharmacists to help them identify codeine dependency, and responsible prescribing practices where prescriptions are required.

Doctors also play a crucial role in recommending codeine and in identifying dependency. As health professionals with long-standing relationships with patients, they are well-placed to tackle addiction but are also in the difficult position of having to refuse or moderate the use of painkillers for people in their own community.

Better training could help them play a more decisive role. A survey of almost 400 medical professionals carried out by CODEMISUSED found that 77% of doctors routinely reviewed patients prescribed codeine, but only 21% said they were confident in identifying codeine dependence. Three-quarters said more instruction on alternative pain management options would be valuable.

The role of educating general practitioners (GPs) in managing addiction is the focus of a separate project, BEAMED. Through a collaboration between Ireland and Canada, researchers are testing a specialised training programme used in Canada in a European context.

‘GPs are well placed to identify and treat mental health and substance use problems,’ said Dr Walter Cullen, professor of urban general practice at University College Dublin (UCD), Ireland.

‘Improving the identification and treatment of addiction-related issues through education and training is a global challenge. The lessons from this programme (in Canada) will be examined to inform future developments in the EU.’

Across Europe, family doctors have a growing role in addiction, ranging from the provision of methadone for opioid users to managing other addictions such as alcohol and nicotine.

The British Columbia Centre on Substance Use has developed an addiction medicine fellowship which equips health professionals to lead state-of-the-art addiction services. By borrowing from this model, services in Ireland and other EU countries can be improved, according to Dr Jan Klimas who works at the University of British Columbia in Canada and UCD.

‘By applying proper training, evidence-based tools and resources, the pool of addiction specialists will increase,’ he said. ‘This will help to identify drug use earlier, preventing its escalation to substance use disorders and reducing the number of patients in need of treatment.’

Source: Horizon: The EU Research & Innovation Magazine

Friday, March 30, 2018

Staying Alive: How To Fight An Opioid Addiction

Staying Alive: How To Fight An Opioid Addiction
By Emily Bazar March 30, 2018

Rule No. 1: Stay alive.
If you or a loved one wants to beat an opioid addiction, first make sure you have a handy supply of naloxone, a medication that can reverse an overdose and save your life.

“Friends and families need to keep naloxone with them,” says Dr. David Kan, an addiction medicine specialist in Walnut Creek who is president of the California Society of Addiction Medicine. “People using opioids should keep it with them, too.”

More than 42,200 Americans died from opioid overdoses in 2016, victims of a crisis that’s being fueled by the rise of a powerful synthetic opioid called fentanyl, which is 30 to 50 times more potent than heroin. Rock stars Prince and Tom Petty had fentanyl in their systems when they died.

People can become addicted to opioids through long-term use, or misuse, of prescription painkillers. In most cases, that leads to heroin use, according to the National Institute on Drug Abuse.

If you’re ready to address your own addiction, or that of a loved one, know that you may not succeed — at first. You probably won’t be able to do it without outside help or medications. And you’ll probably have to take those medications for years — or the rest of your life.

“Getting over a drug addiction is a process. There are going to be ups and downs,” says Patt Denning, director of clinical services and training at the Center for Harm Reduction Therapy in San Francisco and Oakland. “We need to hang with people while they’re struggling. It might take awhile.”

That’s why Denning and others suggest you start with having naloxone on hand, which can help you stay alive through the process.

Last year in San Francisco, about 1,200 potentially fatal overdoses were reversed by regular folks administering naloxone, not doctors, police or paramedics, Kan says.

Naloxone, which can be administered as a nasal spray or injection, is available without a prescription in more than 40 states, including California. Ask your pharmacy if it stocks the drug. Needle exchange programs also offer the medication at no charge, Denning says, as do some public health clinics.

Rehab Doesn’t Work
People addicted to opioids face staggering relapse rates of 80 to 90 percent within 90 days if they try short-term rehab or detox programs that wean them off the drugs without assistance from medications, says Richard Rawson, a UCLA psychiatry professor emeritus.

Rawson warns that rehab can also increase the risk of an overdose, because your body’s tolerance to opioids is lower after you withdraw from them.

“If you leave rehab and take the same dose you used to take, you’re not just going to get high, you’re going to be dead,” he says.

Instead of treating opioid addiction like a curable illness, he and other experts liken it to lifelong, chronic conditions such as diabetes that require ongoing management.

“This isn’t going to be one visit. If you have an addictive disorder, this is going to be the rest of your life,” says Dr. Stuart Gitlow, an addiction specialist in New York City who is past president of the American Society of Addiction Medicine.

Chronic illnesses often require medication. Rawson and others point to two drugs in particular that may help break your addiction: buprenorphine and methadone.

There is some unwarranted stigma attached to these drugs, along with a belief that “you’re just exchanging one addiction for another,” Kan says.

While these medications are actually opioids themselves, they control craving and withdrawal — and help prevent the compulsive and dangerous behavior often associated with addiction.

They also reduce your chances of an overdose, Rawson says. And they protect you from other risks that come with opioid addiction, such as exposure to blood-borne infections from sharing needles, including HIV and hepatitis C.

Essentially, the medications make you “comfortable enough physically” to confront the issues behind your addiction, from anxiety and depression to post-traumatic stress disorder, Denning says.

The federal government agrees.
“Abundant scientific data show that long-term use of maintenance medications successfully reduces substance use, risk of relapse and overdose, associated criminal behavior, and transmission of infectious disease, as well as helps patients return to a healthy, functional life,” according to the Surgeon General’s 2016 report on addiction in America.

To obtain methadone, you must visit a clinic governed by state and federal rules.

“These clinics are not particularly patient-friendly. You have to go every day. You can’t travel,” Denning says. “It takes over your life.”

Buprenorphine, on the other hand, can be obtained from doctors, including primary care physicians, who have undergone training and received federal approval.

“The beauty of buprenorphine is it can be prescribed like any medication out of a doctor’s office,” Denning says.

To find a doctor who prescribes buprenorphine, go to the Substance Abuse and Mental Health Services Administration website at and click on the “Find Help & Treatment” link from the home page. You can search by state and ZIP code.

Though you can receive care from your primary care physician, Gitlow recommends that you also consult with an addiction specialist.

In California, find one by visiting the California Society of Addiction Medicine’s website at and clicking on the “Physician Locator” tab.

If you do not live in California, check the American Academy of Addiction Psychiatry’s website at and click on the “Patient Resources” tab on the home page.

After You Start The Medication …
Once patients start one of the medications, it’s not clear how long they should stay on — a question that deserves further research, Rawson says.

“The longer people stay on treatment, the lower the death rate is and the more they’re able to function,” he says.

Often patients face pressure from family members, who badger them to get off the medications even though it would be better for them to stay on them, Kan says.

“We don’t say to patients who suffer from diabetes … ‘Have you changed your diet enough so you can get off insulin?’” he says.

Kan and other addiction specialists generally don’t encourage medication treatment alone, no matter how long you stay on it. Pairing the medication with therapy or other support, including 12-step programs such as Narcotics Anonymous, can reduce relapse rates further, they say.

Al-Anon and Nar-Anon groups also can be helpful resources for families, Kan adds.

“12-step is something I encourage for everybody. I don’t consider it a treatment, per se. It’s like mutual support,” he says.

Questions for Emily:

Click here to read previous Ask Emily columns. 

This story was produced by Kaiser Health News, which publishes California Healthline, a service of the California Health Care Foundation.