Pauline Anderson

September 27, 2016

SAN ANTONIO — Ketamine, typically thought of as a powerful sedative restricted to surgical use, is now generating a lot of interest among pain management specialists as a useful approach to refractory migraine and complex regional pain syndrome (CRPS).

The use of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, to fight these chronic pain conditions was discussed in separate sessions here at the American Academy of Pain Management (AAPM) 2016 Annual Meeting. (The society's name has recently changed to the Academy of Integrative Pain Management.)

In a presentation focusing on migraine during the meeting, Duren Michael Ready, MD, a headache specialist at Baylor, Scott & White Health, Temple, Texas, cited research showing that intranasal (IN) ketamine 25 mg reduces severity of aura and that IN ketamine 10 to 50 mg is safe and effective for breakthrough pain.

In addition, ketamine can address depression, often seen in pain conditions such as migraine. According to Dr Ready, IN ketamine 50 mg is effective in refractory depression.

"By improving depression, patients feel more able to do things and engage in activities, so the brain is able to get more stimulation, more input, and it's not left to focus on the brain; the brain is wired to pay attention to pain," Dr Ready told Medscape Medical News in an interview.

Ketamine is not for all patients. "It's not something you want to pull out for everyone, but it might it be useful for someone not getting better with typical treatments like the abortives such as triptans or some of the nonsteroidal products such as aspirin or ibuprofen," said Dr Ready. For these patients, "you don't want to go to the other medications that have been shown to induce migraine progression such as the opiates," he added.

These might be patients whose headaches have progressed, he said. "Their nervous system is so totally sensitized to where almost any input is going to bring about pain. For these individuals, the oral medications like the triptans or the nonsteroidals aren't going to be very effective."

Dr Ready stressed that ketamine should be prescribed carefully. He suggested that for a patient who needs an acute therapy for their chronic migraine, "you can have the drug compounded and they can use it for rescue."

But he stressed that, as with other medications, "you want to kind of limit how often patients use it and you also want to keep patients working on their preventive interventions."

Neurologist Hisham Hakim, MD, chairman, American Spine Center, Birmingham, Alabama, who attended the presentation, agreed that experts need to start tapping into alternatives to typical headache therapies to treat patients for whom these approaches haven't worked.

"We need to bring in unusual treatments for those tough cases, such as patients with chronic resistant headache," he said.

In addition to using a topical ketamine cream, migraine patients can use a subanesthetic doses in a nasal spray. "These are not doses at a level that will produce sedation, but at levels that can help block the pain," said Dr Ready.

The nasal metered-dose inhaler delivers 5 to 10 mg per spray, he said.

"You're not trying to achieve sedation; you're trying to saturate some of the receptors — the NMDA receptors — and that's what can happen at subanesthetic doses."

A side effect of ketamine in patients with headache could be hallucinations or having an "out of body" feeling, said Dr Ready.

In a separate presentation, Ben Keizer, PhD, San Antonio Military Medical Center, Texas, and Justin Boge, DO, Evans Army Community Hospital, Fort Carson, Colorado, discussed, among other things, use of ketamine, a schedule III controlled substance, in veterans with comorbid CRPS and post-traumatic stress disorder (PTSD).

CRPS is a debilitating neurologic syndrome characterized by complex and varied dynamic clinical presentation, regional and nondermatomal distribution of symptoms, and pain out of proportion to inciting events, the authors note.

They cited reports of the "remarkable" antidepressant effects of low-dose intravenous ketamine and successful ketamine treatment of patients with PTSD. It's unclear whether the biggest impact is on the PTSD or the CRPS, they noted.

A possible treatment strategy for a patient with both PTSD and CRPS could be ketamine therapy combined with psychotherapy to tackle "core maladaptive fears underlying PTSD" and "fear and avoidance thoughts and behaviors that sustain both PTSD and CRPS," Dr Keizer and Dr Boge write.

Commenting on this growing use of ketamine to manage patients with pain, Robert Bonakdar, MD, director, Pain Management, Scripps Center for Integrative Medicine, La Jolla, California, said it illustrates how he and his colleagues "have transitioned from saying 'that's a really powerful anesthetic' to saying 'if we use it in the right dose and in the right arena, it can be very helpful'" for pain.

Ketamine helps quiet the "hyperexcitability" that is associated not only with chronic migraine and CRPS but also with other pain conditions (such as phantom limb pain) and functional pain disorders (such as fibromyalgia, irritable bowel syndrome, and chronic pelvic pain), said Dr Bonakdar.

"These types of pain conditions, for which we don't have a direct curative measure, are probably existing in a hyperexcitable brain, and ketamine is very helpful for these conditions."

Dr Bonakdar noted how fast the drug can affect refractory depression. "Some of the initial studies showed that refractory depression can, in some cases, be improved within an hour."

On September 2 this year, the World Federation of Societies of Anesthesiologists (WFSA) called for global support for its initiative to protect ketamine's status as "an essential medicine for anesthesia and pain relief, in the face of efforts by China and other countries which have a problem with ketamine abuse — to have the drug included on the United Nations schedule for controlled drugs," the WFSA said in a statement.

Ketamine is used as the sole available safe anesthetic in many parts of the world and is easily transported in situations such as disasters, the WFSA said. "The NGO Médecins Sans Frontières says that its doctors use ketamine as anesthetic and or pain relief in 90% of the Caesarean sections they do, and 95% of trauma surgeries," the statement added.

The UN's Commission on Narcotic Drugs (CND) has so far not made this change, the statement noted. "However, there is worldwide concern that the CND has not closed the subject and appears open to debating the matter at future meetings," the statement noted.

The researchers have disclosed no relevant financial relationships.

American Academy of Pain Management (AAPM) 2016 Annual Meeting. Presented September 24, 2016.

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