Pain Research | Headache NewsBlog

Using AI to predict who will respond to placebo

By: Dr. Mauskop

16-04-2023

Headache medications, Headaches, Pain, Pain Research, Psychology of headaches

Placebo response is a bane of clinical trials but it can be very helpful in practice. A team of American and Canadian researchers used AI to help identify predictors of the placebo response. The results were recently published in Pain, under the title, Predicting placebo analgesia in patients with chronic pain using natural language processing: a preliminary validation study.

Since they used AI for their study, I thought it would be fitting to use ChatGPT to edit their abstract for the lay public.

Patients with chronic pain often experience significant pain relief from placebos (inert pills), and this effect can last for days or even weeks. However, it’s still unclear whether we can reliably predict who will respond to placebo and how to do so. Previous research has shown that people who respond well to placebos tend to talk about their pain and their life in a certain way. In this study, the researchers looked at whether these language patterns can predict who will respond to a placebo before they even receive the treatment, and whether we can distinguish between people who will respond to a placebo versus a real drug.

To do this, they analyzed language patterns from patients with chronic back pain who received a placebo in one study and used this information to build a language model that could predict who would respond to a placebo in a separate study. They found that this language model was able to predict, before treatment, which patients would respond well to a placebo in the second study. These patients reported an average of 30% pain relief from the placebo, while those predicted to be non-responders only experienced a 3% reduction in pain. However, the model was not able to predict who would respond to a real pain medication or who would recover without treatment, suggesting that it specifically predicts response to placebos.

Overall, this study suggests that we may be able to use language patterns to predict who will respond to placebos, which could help researchers design better clinical trials and improve patient care.

Microdosing for chronic pain

By: Dr. Mauskop

14-11-2022

Alternative Therapies, Chronic migraine, Headache medications, Headaches, Migraine, Pain, Pain Research

Psychedelics are being actively studied for depression and post-traumatic stress disorder (PTSD). These trials usually involve hallucinogenic doses. Microdosing psychedelic substances such as psilocybin, lysergic acid diethylamide (LSD), and methylenedioxymethamphetamine (MDMA) has become a popular treatment for depression. Microdosing means that the amount of a psychedelic is too low to cause hallucinations or other overt sensory experiences.

There is an accumulation of evidence that psychedelics can provide pain relief. A case series just published in the journal Pain describes three patients with chronic pain who obtained significant relief from microdosing psilocybin-containing mushrooms.

The first patient was a 37-year-old man with severe pain due to traumatic quadriplegia. He had almost complete relief of pain and was able to stop taking tramadol, an opioid analgesic, diazepam (Valium), and marijuana. The relief was ongoing for six months when he was last seen by the doctors.

The second patient was a 69-year-old woman with complex regional pain syndrome (also known as reflex sympathetic dystrophy) secondary to left leg trauma. She had tried nerve blocks, other invasive procedures, stem cell injections, acupuncture, opioid analgesics, and many other medications, all with no relief. At the time of the published report, microdosing was providing continued significant relief for over a year.

The third patient was a 40-year-old woman with pain in her leg due to degenerative disk disease in her spine. Her pain did not improve with epidural injections, back surgery, muscle relaxants, opioid drugs, and physical therapy. Psychedelic mushrooms had a profound effect on her pain.

Psychedelic mushrooms have been reported by many patients to be effective in the treatment of cluster headaches (see ClusterBusters.org). A small double-blind study by Yale researchers showed a beneficial effect of synthetic psilocybin in treating migraine headaches.

It remains to be proven that sub-hallucinogenic doses of psychedelic drugs provide relief of painful conditions. If proven effective, however, such drugs will offer a much safer option than any opioid and NSAID analgesics, epilepsy drugs, antidepressants, or any other prescription drug. They are very safe even at hallucinogenic doses.

I am often asked about the practical side of using psychedelic mushrooms – where to buy them, how much to take, and for how long. Since the state of NY, unlike some other states, has not legalized or decriminalized the use of psychedelic mushrooms, I cannot answer these questions. Even if it was legal for me to do, I would not have reliable answers until clinical trials give us good data.

Internet-delivered cognitive and behavioral interventions help chronic pain

By: Dr. Mauskop

05-02-2022

Alternative Therapies, Pain, Pain Research, Psychology of headaches

My previous post described a study that found no difference in efficacy among different types of psychosocial interventions for the treatment of chronic back pain. A recent 2020 Cochrane review concluded that there is strong evidence that face-to-face treatments based on cognitive behavioral therapy (CBT) have a small beneficial effect on reducing pain, disability, and distress in people with chronic pain.

A meta-analysis just published in the journal Pain examined the efficacy of CBT delivered via the internet. Australian researchers examined 36 studies with 5778 participants. Most participants were female, and most studies recruited participants from community settings through online advertisements in Western countries.

They concluded that “internet-delivered cognitive and behavioural interventions can result in small significant improvements in interference/disability, depression, anxiety, pain intensity, self-efficacy and pain catastrophizing. Guided interventions may result in greater treatment effects for key outcomes in pain management, including interference/disability, anxiety and pain intensity.”

The meta-analysis showed that guidance by a clinician improves the results. However, this guidance varied across the studies in terms of
how it was provided (e.g., via secure email, SMS messages, telephone calls), the timing and frequency with which it is provided (e.g., weekly, on demand, or at set time points), the amount provided (e.g., brief versus extended), and the professional qualifications and experience of those providing it (e.g., students-in-training, registered psychologists, non-health professionals). There was no difference between the traditional CBT and ACT (acceptance-commitment therapy), confirming the results described in my previous post.

There are several sites that offer CBT courses over the internet. ThisWayUp.org.au and moodGYM.anu.edu.au, online-therapy.com, and others. During the pandemic almost all social workers and psychologists switched to virtual appointments. Lower cost is the advantage of self-directed online CBT courses.

If you see a friend respond to treatment, you are more likely to respond as well

By: Dr. Mauskop

21-10-2021

Alternative Therapies, Headache medications, Migraine, Pain, Pain Research, Psychology of headaches

The placebo effect is a bane of clinical trials. It is, however, a great tool in clinical practice. It is unethical to prescribe an actual placebo but there is no reason not to try to enhance the placebo effect when prescribing any treatment, pharmacological or non-drug.

A new and unique study that was just published in Pain, a journal of the International Association for the Study of Pain, suggests that looking at others who respond to treatment makes people more likely to respond to that treatment as well.

German researchers decided to study what is called social observational learning (SoL). This was a double-blinded randomized controlled clinical trial in 44 patients with chronic low-back pain (CLBP). They compared the effects of observing positive treatment outcomes in a sham or pretend patient versus hearing the same sham patient report neutral effects. In the SoL group, the sham patient told study patients about his improved pain due to amitriptyline and he also demonstrated his improved mobility by bending forwards and sideways. The same sham patient told the control group only that he was taking amitriptyline. The researchers collected data before and after the intervention and two weeks later. After the intervention, pain decreased in both groups with no difference between groups. The SoL group, however, showed a significantly larger decrease in perceived disability.

The authors concluded that “The CLBP patients’ direct observation of positive treatment outcomes in the sham patient appears to have enhanced the treatment effects, while indirect verbal reports of reduced pain did not.”

These findings are not surprising. I often have patients ask for a particular treatment because their friend or relative had a very good response to it. If it is a reasonable treatment for a particular patient, I usually oblige, hoping for an enhanced placebo effect.

A large study shows that the weather affects pain

By: Dr. Mauskop

27-09-2021

Alternative Therapies, Chronic migraine, Headaches, Migraine, Pain, Pain Research

Many migraine sufferers report that their migraines are brought on by the weather. High humidity, high temperatures, and changes in barometric pressure are the most commonly reported triggers. I’ve seen some patients for whom changes in the weather is the only trigger. Research studies looking at this connection, however, have been contradictory.

A very large study just published in Pain, the journal of the International Association for the Study of Pain examined a possible connection between the weather and pain tolerance.

The data from 18,000 Norwegians aged 40 years or older from the general population were examined. All of them underwent pressure pain tolerance (PPT) test using a blood pressure cuff and cold pain tolerance (CPT), tested by immersing the dominant hand in cold water.

The results showed a clear seasonal variation in CPT. Cold pain tolerance was worse during the warmer times of the year compared with January. There was no seasonal variation in PPT.

The authors also found that temperature and barometric pressure have “a causal and dynamic effect on pain tolerance, which supports the common belief that weather affects pain.”

There is not much you can do about the weather except for moving to a place with an unchanging and mild climate. Some of my patients with barometric pressure-induced headaches do respond to acetazolamide (Diamox). This is a diuretic that prevents mountain sickness in climbers. Patients do not need to constantly check the weather forecast. For more information on acetazolamide, see my previous blog post.

Placebo really works, even if you know it’s placebo

By: Dr. Mauskop

30-08-2021

Alternative Therapies, Headache medications, Headaches, Migraine, Pain, Pain Research, Psychology of headaches

The placebo effect is a bane of clinical trials. A drug is considered ineffective if it is only as good as a placebo. And placebo can be quite good. Intriguingly, the placebo effect in clinical trials has been getting stronger over the past few decades. Lately, placebo has been receiving a lot of attention from researchers.

A rigorous study just published in the journal Pain looked at the effect of a placebo when patients were clearly told that they are taking a placebo. These patients were compared to those who were given a placebo in a double-blind study of peppermint oil capsules for irritable bowel syndrome (IBS). These two different types of placebo were compared to a control group of patients who were not given any pills.

Participants treated with an open-label placebo and a double-blind placebo reported similar and clinically meaningful improvements in IBS symptoms. These improvements were significantly greater than in those who were not given any pills. The results were statistically significant for the primary outcome measure (IBS Symptom Severity Scale) as well as for mean global improvement scores.

Twice as many patients in the double-blind placebo group had side effects (mostly gastrointestinal, such as heartburn) than those in the open-label placebo. It is probably because the first group was told about the possible side effects of peppermint oil.

The authors concluded that an open-label placebo “could play a role in the management of patients with refractory IBS”.

Just like migraines, IBS involves central sensitization and hypersensitivity of the nervous system. And just like with migraines, placebo response in clinical trials of IBS tend to be high. This is not to suggest that these conditions are psychological. Especially with migraines, the biological basis is well documented. Psychological factors, however, cannot be ignored. About 40% of patients with chronic pain, including migraines, have a history of emotional, physical, or sexual abuse. Post-traumatic stress disorder of other types also causes hypersensitivity of the central nervous system. Psychological factors can even be the cause of such potentially deadly conditions as broken heart syndrome (Takotsubo cardiomyopathy). It is likely that the placebo effect is stronger in conditions where psychological factors are more pronounced.

It is considered unethical to prescribe a placebo to patients without telling them that they are getting a placebo. This latest study suggests that some patients may improve even if they know that they are taking a placebo.

I do prescribe herbal supplements such as feverfew and boswellia and on a rare occasion, a homeopathic remedy, all of which lack rigorous proof of their efficacy. For that matter, many drugs we prescribe for migraines lack such definitive proof. I would suggest that we should first prescribe less harmful unproven remedies rather than unproven prescription drugs.

Chronic pain causes cognitive decline

By: Dr. Mauskop

17-07-2021

Brain disorders, Chronic migraine, Pain, Pain Research

Many patients with chronic migraines complain of memory, word-finding, and other cognitive difficulties. I tell them that once we find an effective treatment for their migraines, their cognitive abilities should improve. I explain that the barrage of pain messages disrupts the normal flow of information in the brain.

“Association between chronic pain and long-term cognitive decline in a population-based cohort of elderly participants” is the title of a study published in a recent issue of the journal Pain. The French researchers followed elderly chronic pain patients for up to 15 years.

They concluded that “Chronic pain is associated with a higher cognitive decline, particularly in processing speed. This result reinforces the importance of actively treating chronic pain with pharmacological and nonpharmacological strategies to prevent its consequences, including cognitive consequences.”

This also applies to chronic migraines. Fortunately, we have many new and not so new highly effective pharmacological and non-drug therapies that can provide relief to well over 90% of chronic migraine suffers. Check out my new book, The End of Migraines: 150 Ways to Stop Your Pain.

The pendulum swings and hits hard patients on opioid drugs

By: Dr. Mauskop

17-05-2021

Brain disorders, Chronic migraine, Headache medications, Headaches, Migraine, Pain, Pain Research

The opioid epidemic has claimed many lives. Overprescribing by doctors has certainly played a role. The push to use opioids more liberally started in the late 1980s. This promotion by many pain experts even led to pain being adopted as the fifth vital sign. One impetus for this push was the mistaken belief in the low rates of addiction when opioids are used to treat pain. Another was the results of surveys of patients being discharged from hospitals. Poor pain control was the main complaint of 40% of such patients. Centers for Medicare & Medicaid Services (CMS) got into the act as well and included good pain control as one of the measures required for the recertification of hospitals. In January 2018, however, the three survey questions about pain management were replaced by three questions about communication about pain. In October of 2019, even these three items about communication about pain were completely removed from the CMS’ HCAHPS Survey. So hospitals and doctors no longer need to worry about relieving pain and the suffering that goes with it. Doctors have to worry more about losing their license or even being put into jail. I’ve testified in front of a disciplinary panel on behalf of a doctor who was at risk of losing his license. An adult patient’s mother complained to the state health department about her son getting prescriptions for opioid drugs. In this case, the doctor was exonerated but the financial and the emotional toll will certainly make him very unlikely to continue prescribing opioids drugs.

These drugs, despite their potential for causing addiction and other side effects, are life-savers for many people. When used judiciously and as part of a multidisciplinary approach, they can provide not only improved quality of life but can make a difference between disability and normal functioning.

A study just published in the journal Pain looked at the difficulties patients taking opioid drugs have in finding a primary care doctor.

This study examined if primary care clinics “are more or less willing to accept and prescribe opioids to patients depending on whether their history is more or less suggestive of aberrant opioid use”. They conducted an audit survey of primary care clinics in 9 states from May to July 2019. They had simulated patients call the clinics and give one of two scenarios for needing a new provider: their previous physician had either (1) retired or (2) stopped prescribing opioids for unspecified reasons. Of 452 clinics responding to both scenarios (904 calls), 193 (43%) said their providers would not prescribe opioids in either scenario, 146 (32%) said their providers might prescribe in both, and 113 (25%) responded differently to each scenario. Clinics responding differently had greater odds of willingness to prescribe when the previous doctor retired than when the doctor had stopped prescribing.

The authors concluded that “…primary care access is limited for patients taking opioids for chronic pain.” and that “This denial of care could lead to unintended harms such as worsened pain or conversion to illicit substances.”

Hopefully, the pendulum will soon begin moving closer to the middle. Another hope is that the researchers will finally discover the holy grail of pain management – a non-addictive pain medicine with few other side effects.

The description of neuropathic pain predicts response to Botox

By: Dr. Mauskop

18-04-2021

Botox, Brain disorders, Pain, Pain Research

The goal of personalized medicine will be achieved through the exponential growth of computing power. Epigenetics, pharmacogenomics, and machine learning are some of the approaches that are being driven by our ability to process massive amounts of data. Unfortunately, it may take another decade or two before we can offer our patients truly personalized medicine.

Until then, we still have to rely on clinical skills. In a study just published in the journal Pain, D. Bouhassira and his colleagues were able to predict the response of neuropathic pain to Botox injections. The prediction was based on a specific combination of symptoms and signs. They used the Neuropathic Pain Symptom Inventory (NPSI) in 628 patients to identify three distinct clusters of patients. The first group had a more severe pinpointed pain, the second one had more evoked pain, and the third had a higher score for deep pain.

The study included adult patients who had experienced pain for at least three months with a mean pain intensity three or greater on a 0 to 10 numerical rating scale. In more than 85% of the patients, neuropathic pain was due to a traumatic or surgical nerve injury. In the rest, it was due to postherpetic neuralgia (shingles).

The researchers used these three groupings to predicting treatment response through the analysis of their two previous controlled trials of Botox. They found significant effects of Botox compared to placebo in clusters 2 and 3, but not in cluster 1. They also developed and performed a preliminary validation of a web-based version of the NPSI and algorithm for the stratification of patients in both research and daily practice.

Botox is not yet approved by the FDA for the treatment of neuropathic pain. This means that insurance companies are unlikely to pay for it. Besides the pain of shingles, neuropathy, injured nerves (I’ve treated two patients with post-amputation pain), we use Botox “off label” to treat trigeminal neuralgia, cluster headaches, hemicrania continua, numular headaches, and other painful conditions. In one of my patients, even headache due to a large but benign brain tumor responded to Botox.

Botox helps such a wide variety of headaches and other painful conditions probably due to its proven effect on sensory nerve endings.

In treating migraine headaches with Botox, there were several attempts to find clinical predictors of response. More recent onset of chronic migraine and fewer days with migraine have been identified as predictors of a better response. . There have been also suggestions that eye pain was a good predictor of response to Botox. Patients with”exploding” (pressure from inside-out) headache may be less responsive than those with “imploding” (pressure from outside-in, or constricting pain) headache.

When studied in large groups, these features might have some predictive value. But it is not anywhere close to 100% or even 70%. Therefore, when dealing with an individual patient we would try Botox in patients with chronic migraines regardless of the presence or the absence of any of these symptoms.

Bidirectional association between loneliness and pain

By: Dr. Mauskop

21-03-2021

Brain disorders, Pain, Pain Research, Psychology of headaches

COVID-related lockdowns have saved many lives. We don’t yet fully appreciate, however, the other side of the ledger – the harms the lockdowns have caused. These include delays in diagnosing cancers, alcohol and drug abuse, depression, anxiety, deprivation of schooling and socialization in children, and worsening of pain and headaches. The latter not only because of lack of access to care but also due to the effect of loneliness.

Prior studies have shown that loneliness is consistently associated with pain. A study by British researchers published in the current issue of the journal Pain examined the question of whether loneliness worsens pain or pain leads to loneliness.

Drs. Anna Loeffler and Andrew Steptoe studied 4,906 men and women (mean age was 65) over a period of four years. They also looked at the role of inflammation in these people. Pain was defined by reports of being often troubled by pain at a moderate or severe intensity. Loneliness was measured using a standard scale. The researchers took into account age, sex, ethnicity, educational attainment, wealth as a marker of socioeconomic resources, marital status, physical activity, degree of mobility, and depressive symptoms.

They found that baseline loneliness was associated with pain four years later. Similarly, baseline pain independently predicted loneliness four years later. The likelihood of pain was increased when at the baseline loneliness was accompanied by an increase in an inflammation marker, C-reactive protein (CRP). On the other hand, inflammation did not predict future loneliness. Both pain and loneliness are distressing experiences that impact well-being and quality of life. The researchers concluded that the relationships between pain and loneliness are bidirectional.

100 Migraine Drugs, A to Z: Low-dose naltrexone

By: Dr. Mauskop

06-08-2020

Alternative Therapies, Chronic migraine, Pain, Pain Research

Naltrexone is similar to naloxone, a drug used to reverse the effect of narcotic (opioid) overdose. Naltrexone is not used to reverse the effect of an overdose, but to treat opioid and alcohol dependence. (LDN) and is given as a monthly injection or a daily pill. Naltrexone blocks the body’s own endogenous morphine (endorphin) receptors. In theory, this should make the pain worse. However, low-dose naltrexone (LDN) seems to have the opposite effect. It is possibly explained by the fact that a small amount of naltrexone blocks the endorphin receptors for a short time, during which the body begins to make more endorphins in an attempt to overcome this block. After the effect of naltrexone wears off, this extra amount of endorphins provides relief of pain and by blocking other receptors (such as Toll-like receptor 4) and reducing inflammation, potentially produces other beneficial effects, most of which are not scientifically proven.

Inflammatory bowel disease (Crohn’s disease and ulcerative colitis) do seem to respond to LDN.

A study of 27 patients with chronic central pain syndromes at the Stanford Pain Management Clinic published in The Journal of Pain concluded that “The significant findings of decreased average pain scores and depression and improved physical function after prescribing this well-tolerated, inexpensive medication provides justification for larger, controlled trials in patients with central sensitivity syndromes.” Some of these central sensitivity syndromes include migraine, fibromyalgia, irritable bowel syndrome, chronic back pain, and other.

Naltrexone is available only in a 50-mg tablet, while LDN is started at 1.5 mg nightly for a week, then 3 mg nightly for a week, and then, 4.5 mg nightly. This regimen requires a compounding pharmacy to make capsules containing 1.5 mg for the first two weeks and then, capsules with 4.5 mg. Some of my patients went up as high as 9 mg nightly. Compounded drugs tend to be more expensive than factory-made generics but because naltrexone itself is cheap, the cost of 30 capsules can be as low as $50.

Because the dose is low, side effects are rare. These include vivid dreams and insomnia and if these occur, the medicine can be taken in the morning.

WTF? Do we need another study of swearing for the relief of pain?

By: Dr. Mauskop

25-07-2020

Alternative Therapies, Brain disorders, Chronic migraine, Pain, Pain Research, Psychology of headaches, Science of Migraine

Having given Botox injections to thousands of patients, I know that some patients tolerate pain better if they curse during the procedure.

A British psychologist Richard Stephens seems to have made a career out of studying the effect of cursing on pain. His first paper Swearing as a response to pain, appeared in 2009 in NeuroReport. It showed that swearing improves pain tolerance in volunteers whose hand was submerged in icy water. His next paper, which I mentioned in a post in 2011, Swearing as a Response to Pain—Effect of Daily Swearing Frequency was published in The Journal of Pain.

In this study, Stephens looked at the effect of repeated daily swearing on experimental pain. The volunteers were again subjected to pain by submerging their hand into icy water. And they again showed that swearing reduces pain. However, people who tended to swear frequently throughout the day had less of a pain-relieving effect than those who did not.

His latest paper, Swearing as a Response to Pain: Assessing Hypoalgesic Effects of Novel “Swear” Words, was just published in the Frontiers in Psychology. The authors show that made-up “swear” words are not as effective as the good old four-letter f-word.

The conclusion of this 6,500-word research paper suggests that there is still a lot more swearing …er … I mean, studying to be done on this subject. Whether this is a good use of the British taxpayers’ money is another matter. Is the ultimate goal to save the British National Health Service money by replacing pain medications with scientifically validated swear words?