FDA Okays First Single-Entity Extended-Release Hydrocodone.


The US Food and Drug Administration (FDA) has approved the first single-entity extended-release formulation of hydrocodone bitartrate (Zohydro ER, Zogenix Inc) for the management of pain severe enough to require daily around-the-clock long-term treatment and for which alternative options are inadequate.

“Zohydro ER, a Schedule II controlled substance under the Controlled Substances Act, is the first FDA-approved single-entity (not combined with an analgesic such as acetaminophen) and extended-release hydrocodone product,” a statement from FDA released today notes.

“Zohydro ER will offer prescribers an additional therapeutic option to treat pain, which is important because individual patients may respond differently to different opioids.”

This formulation belongs to the class of extended-release/long-acting (ER/LA) opioids, the statement notes. “Due to the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with ER/LA opioid formulations, Zohydro ER should be reserved for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain,” the FDA release said.

It is not approved for as-needed pain relief.

In addition, the labeling approved for this drug conforms to updated labeling requirements for all ER/LA opioids announced by the FDA on September 10 and reported at that time by Medscape Medical News, the first opioid to be labeled in this way, the statement notes.

“The new class of labeling and stronger warnings will more clearly describe the risks and safety concerns associated with ER/LA opioid analgesics, along with the appropriate use of these medications,” the FDA said. “These warnings are expected to improve the safety of all such medicines by encouraging more appropriate prescribing, patient monitoring, and patient counseling practices.”

Schedule II drugs can be dispensed only by prescription, and no refills are allowed. Stringent record-keeping, reporting, and physical security requirements are also in place for these substances.

The FDA will require postmarketing studies of this agent to assess the “known serious risks of misuse, abuse, increased sensitivity to pain (hyperalgesia), addiction, overdose, and death associated with long-term use beyond 12 weeks,” the FDA release said. “These studies will also be required for other ER/LA opioid analgesics.”

Safety of this new formulation of hydrocodone is based on clinical studies that have included more than 1100 patients with chronic pain. Efficacy is based on a clinical study that enrolled more than 500 patients with chronic low back pain and showed a significant improvement in chronic pain vs placebo.

It will also be part of the ER/LA Opioids Analgesics risk evaluation and mitigation strategy (REMS) approved in 2012. The REMS requires companies to make educational programs on how to safety prescribe these agents to healthcare professionals and provide medication guides and patient counseling documents with information on safe use, storage, and disposal of ER/LA opioids.

The most common adverse effects of this single-entity hydrocodone are constipation, nausea, somnolence, fatigue, headache, dizziness, dry mouth, vomiting, and pruritus.

In December 2012, FDA’s Anesthetic and Analgesic Drug Advisory Committee of independent experts voted 11 to 2, with 1 abstention, to recommended against approval of this agent for the treatment of moderate to severe chronic pain.

Most panel members voted that the drug had met regulatory requirements for safety and efficacy, as indicated by their responses to questions on efficacy and safety. However, for the last question voted on — “Based on the data presented and discussed today, do the efficacy, safety and risk-benefit profile of Zohydro ER support the approval of this application?” — most had negative responses.

The main concern of those voting against approval was that the potential for abuse of these agents; because the product does not include acetaminophen, they feared the potential for abuse might be even greater.

Source: Medscape.com

Codeine risky for kids after certain surgeries, FDA says.


Children who are given codeine for pain relief after surgery to remove tonsils or adenoids are at risk for overdose and death, U.S. health officials said.

The U.S. Food and Drug Administration said a new boxed warning—the agency’s strongest caution—will be added to the labels of codeine-containing products to warn about this danger.

The FDA strongly recommends against the use of codeine to manage pain in children after surgery to remove tonsils or adenoids, and suggests that doctors use an alternate pain reliever. The agency also said parents and caregivers need to be aware of the risks and ask for a different pain medicine if their children are prescribed codeine after having their tonsils or adenoids removed.

Codeine is an opioid (narcotic) medication used to treat mild to moderate pain and is often prescribed to children after tonsil or adenoid removal. However, some children have died after being given codeine within the recommended dose range.

 

In August 2012, the FDA warned about the danger in children who are “ultra-rapid metabolizers” of codeine, which means their liver converts codeine to morphine in higher-than-normal amounts. High levels of morphine can result in potentially fatal breathing problems.

Since then, a safety review by the FDA identified 10 deaths and three overdosesassociated with codeine that occurred among children in the United States between 1969 and May 2012. Many of these children were recovering from surgery to remove tonsils or adenoids.

All of the children, aged 21 months to 9 years old, received doses of codeine within the normal dose range. Signs of morphine overdose developed within one to two days after the children began taking codeine, the FDA said in an agency news release.

 

Codeine is available by prescription either alone or in combination with acetaminophen and aspirin, and in some cough and cold medications.

When prescribed to treat pain, codeine should not be given on a fixed schedule, but only when a child needs relief from pain. They should never receive more than six doses in a day, the FDA said.

Children receiving codeine for pain should be closely monitored for signs of morphine overdose. These include: unusual sleepiness, such as being difficult to wake up; confusion or disorientation; breathing problems; and blueness on the lips or around the mouth

Girl who feels no pain could inspire new painkillers.


A girl who does not feel physical pain has helped researchers identify a gene mutation that disrupts pain perception. The discovery may spur the development of new painkillers that will block pain signals in the same way.

People with congenital analgesia cannot feel physical pain and often injure themselves as a result – they might badly scald their skin, for example, through being unaware that they are touching something hot.

By comparing the gene sequence of a girl with the disorder against those of her parents, who do not, Ingo Kurth at Jena University Hospital in Germany and his colleagues identified a mutation in a gene called SCN11A.

This gene controls the development of channels on pain-sensing neurons. Sodium ions travel through these channels, creating electrical nerve impulses that are sent to the brain, which registers pain.

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Blocked signals

Overactivity in the mutated version of SCN11A prevents the build-up of the charge that the neurons need to transmit an electrical impulse, numbing the body to pain. “The outcome is blocked transmission of pain signals,” says Kurth.

To confirm their findings, the team inserted a mutated version of SCN11A into mice and tested their ability to perceive pain. They found that 11 per cent of the mice with the modified gene developed injuries similar to those seen in people with congenital analgesia, such as bone fractures and skin wounds. They also tested a control group of mice with the normal SCN11A gene, none of which developed such injuries.

The altered mice also took 2.5 times longer on average than the control group to react to the “tail flick” pain test, which measures how long it takes for mice to flick their tails when exposed to a hot light beam. “What became clear from our experiments is that although there are similarities between mice and men with the mutation, the degree of pain insensitivity is more prominent in humans,” says Kurth.

The team has now begun the search for drugs that block the SCN11Achannel. “It would require drugs that selectively block this but not other sodium channels, which is far from simple,” says Kurth.

Completely unexpected

“This is a cracking paper, and great science,” says Geoffrey Woods of the University of Cambridge, whose team discovered in 2006 that mutations in another, closely related ion channel gene can cause insensitivity to pain. “It’s completely unexpected and not what people had been looking for,” he says.

Woods says that there are three ion channels, called SCN9A, 10A and 11A, on pain-sensing neurons. People experience no pain when either of the first two don’t work, and agonising pain when they’re overactive. “With this new gene, it’s the opposite: when it’s overactive, they feel no pain. So maybe it’s some kind of gatekeeper that stops neurons from firing too often, but cancels pain signals completely when it’s overactive,” he says. “If you could get a drug that made SCN11A overactive, it should be a fantastic analgesic.”

“It’s fascinating that SCN11A appears to work the other way, and that could really advance our knowledge of the role of sodium channels in pain perception, which is a very hot topic,” says Jeffrey Mogil at McGill University in Canada, who was not involved in the new study.

Source: http://www.newscientist.com

Testosterone reduced pain perception in hypogonadism.


During a press conference here at ENDO 2013,Shehzad S. Basaria, MDmedical director of the section of men’s health, aging and metabolism at Brigham and Women’s Hospital, Harvard Medical School, said testosterone therapy administered to men with opioid-induced androgen deficiency led to a decrease in pain perception on Quantitative Pain Testing (QST) in the pain laboratory.

Basaria and colleagues randomly assigned 65 men (mean age, 49 years; BMI: 33 kg/m2) with an androgen deficiency to 5 g transdermal testosterone gel (n=36) or placebo (n=29) for 14 weeks. Abstract data indicate baseline total testosterone (228 ng/dL) and free serum testosterone levels (44 pg/mL) increased significantly among those assigned to testosterone.

At 12 weeks, patients randomly assigned to testosterone displayed significant improvements to pressure pain thresholds (P<.031), mechanical pain intensity (P=.049) and cold pain after-sensations (P=.08), according to data.

Clinical pain perception, as measured by a validated questionnaire, was not different between the two groups, Basaria said.

“Previous data suggest that improvement in pain perception and tolerance on QST testing generally precedes improvement in clinical pain. A longer study might have shown improvement in clinical pain as well,” Basaria said.

These findings suggest that testosterone therapy administered to men with opioid-induced androgen deficiency led to a greater reduction in pain sensitivity compared with placebo. However, further trials examining the anti-nociceptive role of testosterone are warranted. In an interview with Endocrine Today, Basaria said that the most important message to clinicians would be not to initiate testosterone treatment solely for the treatment of pain. He and colleagues are currently looking at longer term studies that may examine improvements in clinical pain perception as well.

Clinicians should become more aware of this condition called opioid-induced androgen deficiency. Many clinicians do not appreciate that testosterone levels are reduced in a significant number of men who are on opioid analgesics. In some men, testosterone levels are suppressed in castrate range,” Basaria said. “It’s important for clinicians when they have patients in their clinic on opioids to pay attention to complaints of sexual dysfunction, fatigue or decreased energy. Testosterone levels should be checked as these men might benefit from testosterone therapy.” – by Samantha Costa

Source: Endocrine today