Pain - What is Pain?

Pain - What is Pain?

We all get. As I author this, I have a weird ‘rib pain’ for no apparent reason. No idea what I have done, and in fact have done nothing to hurt it to the best of my knowledge. People even wake up with pain for no reason. Well, there is a reason but we just don’t know what the reason is. Ok, you fall down the stairs and you are in pain. In fact, it would be kinda weird if you didn’t feel pain falling down stairs.

In this podcast, we are talking about mostly chronic pain. That is the worse kind. It is the pain that is always with you, day and night, stopping you from life and sometimes, even sleeping. And we are talking mostly about the unexplained pain. Not ‘I hit my finger and it is sore’ pain but the back pain, neck pain etc. that exists due to a passed injury that is explained or ‘it just hurts’ scenario.

Neuropathic Pain – The worst type of pain

Despite a significant amount of research, the treatment of neuropathic pain remains a major challenge for pain specialists and primary care physicians. In the USA, it has been estimated that 6–10% of the population suffers from pain with neuropathic signs and symptoms. Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system. Many patients continue to experience neuropathic pain symptoms despite adequate trials of analgesics from multiple classes of neuropathic agents.

These treatment failures with anti-neuropathic pain agents may be due to lack of analgesic efficacy, intolerance, or contraindications to various classes of medications. Patients with poorly controlled neuropathic pain have significantly poorer health status and increased symptoms of anxiety and depression. On a societal level, neuropathic pain is associated with significant societal costs resulting from higher healthcare utilization, disability, and lost productivity.

Clinically, doctors have noticed a broad spectrum of symptoms described in patients with neuropathic pain, and similarly varied patient response to the available treatments. There have been many efforts to subtype neuropathic pain in order to predict treatment response based on clinical characteristics of the pain symptoms; however, developing effective, reproducible treatment plans for various neuropathic pain subtypes has proven difficult.

What is Neuropathic Pain

In neuropathic pain states, maladaptive changes occur in response to injury and result in the afferent pain pathways deviating from their normal function of alerting the brain to actual or potential tissue damage. The neuropathic pain syndrome is characterized by:

  1. An increase in afferent nerve spontaneous activity and
  2. An exaggerated or abnormal response of the central or peripheral nervous system to afferent input or stimuli.

The initial injury to the central or peripheral nervous system that leads to neuropathic pain can be caused by various insults including physical trauma (herniated disc, compression by a tumour), toxin exposure (chemotherapy, alcohol, heavy metals), infection (HIV, herpes zoster), metabolic abnormalities (diabetes, vitamin deficiencies), and abnormal immune system activation (multiple sclerosis). Although neuropathic pain is a complex disorder seen in various disease states, there are likely common mechanisms occurring in response to nerve injury may underlie the classic symptoms experienced in patients with neuropathic pain.

The classic solution for bad pain – the rise of the opioids

Its is simple. After a consultation with a medical doctor, your can grab a script for your pain and head to the chemist and legally grab some opioids and bang – your pain is better. I mean, that seems to be the best way to kill the pain. Right?

An amazing scientific paper titled “Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep” published this year in the prestigious American Journal of Medicine as seriously ‘belled the cat’.

The History of the Opioid

Extracts of the poppy plant have been used for medicinal purposes since the Sumerians named it the “joy plant” 5,000 years ago. By the time of the American Revolution, an alcohol-based tincture of 10% powdered opium called “laudanum” was widely prescribed in the U.S. and many became addicted. Morphine was isolated from opium about 50 years before it caused “Soldier’s Disease,” an epidemic of addiction during the Civil War. Bayer Pharmaceuticals marketed heroin in 1874 as an analgesic and claimed it was less addictive than other opioids, claims made about the new opioids to follow. During this period, opium, heroin, and cocaine were used in over the counter (OTC) patent medicines and sold OTC in “emergency kits” equipped with hypodermic syringes and needles. By 1925, there were an estimated 200,000 heroin addicts in the U.S.

“Purple Haze”

The problem of opioid addiction led to passage of federal legislation to control it in 1906, 1909, 1914, and 1924. Tolerance for illicit drug use increased after young people smoked marijuana in public and Jimi Hendrix followed his psychedelic version of the national anthem with his song, “Purple Haze” at the 1969 Woodstock Music and Art Fair. By 1971, 15% of soldiers in Vietnam had become heroin addicts. In response, President Nixon declared drug addiction “public enemy number one” in 1972 and established federally supported methadone clinics, only to have methadone quickly become a drug of abuse. Around 1996, the confluence of a new pain movement and the pharmaceutical industry were associated with a dramatic escalation of prescription opioid use, abuse, and opioid-related deaths in the U.S.

Big Pharma – Addiction is no problem

In 1980, a one paragraph “Letter to the Editor” in the New England Journal of Medicine reported that of 11,882 hospitalized patients treated with narcotics, less than 1% of them became addicted. The letter was subsequently “uncritically cited” in 439 articles published in scientific journals. Meanwhile, a shared interest in better management of cancer pain led Raymond Houde, M.D., Katherine Foley, M.D., and Russell Portenoy, M.D. at Cornell University-Weill Medical College to become leaders in the American Pain Society (APS). Two of them concluded that opioid maintenance therapy for chronic noncancer pain was safe and humane. The APS became an advocacy group for opioid treatment of pain and eventually received most of its support from Purdue Pharma, maker of the opioids, MS Contin® and OxyContin®.

The 5th Vital Sign

In 1995, the APS proposed that pain be measured as “The 5th Vital Sign” and trademarked the term. That society published a consensus statement with the American Academy of Pain Medicine in 1997 and declared that there was insufficient evidence to show that addiction occurs when opioids are appropriately prescribed for the treatment of pain. In 2010, the International Association for the Study of Pain added a patient’s rights component to the pain movement when it declared that all patients were entitled access to pain management and treatment, including opioids. Another advocacy group, the American Pain Foundation organized email campaigns to media outlets they determined to be biased against opioids for pain treatment at a time when it received 90% of its funding from the drug and device industry. Many “thought leaders” from pain societies gave Pharma-supported lectures to provider groups to encourage treatment of pain with opioids. The APS was joined by the Veterans Affairs Medical System (VA), the Joint Commission for Accreditation of Health Organizations (JCAHO), now the Joint Commission (TJC), the American Medical Association (AMA), the American Academy of Family Physicians (AAFP) and patient advocacy groups in support of Pain as the 5th Vital Sign. Opioid manufacturers and pain management advocates then convinced the U.S. Congress to declare “A Decade of Pain Control and Research” in 2000.

The New Decade of Pain Relief

By 2001, new TJC Pain Management Standards used as a component of hospital accreditation and reimbursement were implemented and required pain to be assessed and addressed in all hospitalized patients. The commission also implemented its own pain initiative and developed educational materials for it with support from Purdue Pharma and the National Pharmaceutical Council, Inc (NPC). These included the monograph Improving the Quality of Pain Management through Measurement and Action which advocated opioid use for pain and was cobranded with the logos of TJC and NPC. A nurse developed and copyrighted the Wong Baker Facial Scale that allowed patients to grade their pain from 1-10 by choosing faces that smiled or frowned, a subjective measure that soon came to be used as an objective one.

The VA mandated the measurement of Pain As the 5th Vital Sign and be addressed in every clinical encounter in 1999. In 2016, as opioid deaths exploded Physicians for Responsible Opioid Prescribing petitioned TJC to stop their support of opioid use and claimed their pain standards “foster dangerous pain control practices” which “often lead to the inappropriate prescribing of opioids” and “disastrous consequences.”

Pain Intensity Guide – Flawed

A 2015 opinion piece noted the physiological futility of using pain intensity to guide pain treatment and the need to return to the basics of pain management, which were already outlined in a 2010 National Institute of Health Pain Initiative. All of this this eventually led to the 2011 Institute of Medicine report, Relieving Pain in America. About the same time, both the AMA and the AAFP voted to rescind their previous support of pain as the 5th Vital Sign.

The actions of three New York City psychiatrists, the Sackler brothers, played a major role in this story. Dr. Arthur Sackler (D-1987) became a wealthy pharmaceutical marketing executive, publisher of medical trade publications, and father of direct-to-physician marketing. He and his brothers, Mortimer (D-2010) and Raymond (D-2017), purchased Purdue Frederick, a New York drug manufacturer that produced an ear wax remover, a laxative, Betadine®, and a tonic that was 11% alcohol under the name Purdue Pharma, their first new product was the long acting morphine, MS Contin® released in 1984, followed by OxyContin®, a long acting oxycodone.

FDA Failure - Theory of Pseudo-Addiction and the Rise OxyContin

After FDA approval in 1995, OxyContin® was marketed as a “less addictive opioid.” OxyContin® was launched only after the Sackler brothers deployed a carefully considered marketing plan using a 600-person sales force and a list of over 90,000 physicians judged likely to prescribe OxyContin®. Physicians received free trips to exotic locations to hear paid members of the Purdue “Speakers Bureau” give talks supporting opioid use for chronic pain and patients received coupons for an up to 30-day supply of OxyContin® for free. Both the unsubstantiated “Theory of Pseudo-Addiction” suggesting that drug seeking by pain patients treated with opioids reflected under treatment of pain and the report of a 1% addiction rate of opioids were included in OxyContin® marketing. These same erroneous claims were included in a publication of opioid use for pain management by the Federation of State Medical Bonds (FSMB) sponsored by Purdue Pharma. In 2007, Purdue paid $630 million dollars to settle FDA claims for false marketing of OxyContin® and several company officials paid an additional $34 million in fines. More FDA investigation continued and opioid makers and distributors looked for relief.

The ‘Paid for’ Policy

The Pain Policy Study Group (PPSG) composed of social science faculty at the University of Wisconsin, Madison received $2.5 million dollars in grants from the pharmaceutical industry, including $1.6 million dollars from Purdue Pharma in the process of its work on opioids prescribing policies. In 2002, the PPSG reported a 10-year collaboration with the FSMB to “update and clarify state medical board policies on the use of opioid analgesics to treat pain.” Their report was used to develop Model Guidelines for the FSMB to address “prescribing of opioid analgesics for pain and physicians fears of regulatory scrutiny.” In 2003, Purdue provided $100,000 for the printing of 300,000 widely distributed copies of the FSMB Model Guideline, which was highly supportive of opioid use for chronic pain and used to develop opioid prescribing policies by most state boards. The Guidelines were developed in the absence of high quality scientific studies and reflected the opinions of the pain management community who collaborated on their formation.

The Watch Dog Failures Continue

The Controlled Substance Act (CSA) of 1970 relaxed the anti-opioid portions of the Harrison Narcotics Act of 1914 and recognized that opioids had legitimate medical purposes. It established the U.S. Drug Enforcement Agency (DEA) to set production quotas and to monitor and control diversion and excessive production of narcotics. In response to the pain movement, the DEA joined with 21 healthcare organizations in 2001 to call for improved approaches to assure that prescription opioids were available for medical use and prevented from diversion. Surprisingly for a drug enforcement agency, they noted that pain was undertreated and that opioids were the most effective treatment for many patients. Between 1996 and 2007, the Food and Drug Administration (FDA) approved increases in U.S. production of the opioids hydrocodone four-fold, fentanyl ten-fold, and hydromorphone four and a half-fold, but sanctioned less than 0.1% of physicians for narcotic prescribing violations from 1999 to 2003.

Fentanyl – 1990’s most powerful narcotic

Fentanyl, an opioid 80 times more potent than heroin, was brought to market in the U.S. as Duragesic® by Janssen Pharmaceuticals, now owned by Johnson & Johnson, Inc. In the early 1990s, drug dealers began mixing fentanyl with heroin to produce a greater high. After 350 related deaths occurred between 2005 and 2007 in Cook County, Illinois, the combination came to be noted as, “Drop Dead.” By 2016, half of overdose deaths in Illinois were fentanyl-related. When overproduction of fentanyl by the U.S. companies was finally curtailed, chemists in China produced fentanyl in large quantities and developed countless derivatives made available to heroin producers in Mexico and drug users in the U.S. by mail and otherwise. By 2016, carfentanil, initially used to tranquillize elephants and 100 times more potent than fentanyl, was a frequent cause of drug overdoses in Ohio, New York, Pennsylvania, Florida and neighbouring states.

Lessons Learned

The lessons learned from this opioid epidemic are many. For organized medicine, the principal one seems old. That is, making medical treatment recommendations, policies and decisions without solid scientific data is dangerous for all concerned. Those who are most comfortable doing so are likely to have conflicts of interest, ethical issues, and greed. The opioid epidemic has now been declared a “national emergency” when many of the questions about the biology of pain, the treatment of acute and chronic pain, and the treatment of opioid addiction remain unanswered. The course of the epidemic to date reflects our ignorance of the neurobiology of the brain’s reward system and the need for investment in basic and clinical research to understand why drugs of abuse are so attractive to so many. The National Academies have proposed a way forward. We should all follow their suggestions.

History of Medicinal Cannabis


The use of cannabis for medicinal purposes dates back over 5000 years. Its use as an analgesic has been documented in the world’s oldest pharmacopeia, the Chinese pen-ts’ao ching, and cannabis was widely used in Indian Ayurvedic medicine for neuralgia, headache, toothache, and other maladies as early as 1000 B.C. Cannabis was introduced to Western medicine following the 1839 publication of a book titled On The Preparation of the Indian Hemp, or Gunjah by William O’Shaughnessy, an Irish physician who had served the British forces in India and experimented with the use of medical cannabis.

Following this introduction, cannabis use as medicine became widespread throughout Europe and America in the mid-ninetieth and early twentieth centuries. Pharmaceutical companies marketed various forms of cannabis tinctures and extracts. In the United States Dispensatory as early as 1845, cannabis was noted to be “capable of producing most of the therapeutic effects of opium, and may be employed as a substitute for that narcotic, when found to disagree with a patient from some peculiarity of constitution”. In the early twentieth century, the development of synthetic pharmaceuticals such as opioids, nonsteroidal anti-inflammatory agents, and barbiturates, coupled with increased federal restrictions and taxation of cannabis, led to a significant decrease in cannabis use for most of the rest of the century.

The latter half of the twentieth century saw the discovery of the endocannabinoid system, subsequent research on the pharmacology of cannabinoids, and growing scientific evidence supporting the efficacy of cannabis for pain. These findings, along with changing social perceptions and the spread of medical marijuana laws, have led to a resurgence of interest in its therapeutic properties.

The Endocannabinoid System

The endocannabinoid system (ECS) has been shown to play an integral role in the regulation of neuropathic pain and operates via multiple mechanisms involving neuromodulation and immunomodulation at peripheral, spinal, and supraspinal levels. The ECS consists of endogenous cannabinoids, their receptors, and the enzymes responsible for their synthesis, regulation, transport, and metabolism. Three types of cannabinoids are recognized in the literature: phytocannabinoids derived from the cannabis plant, synthetic cannabinoids which are synthetically generated compounds targeting various components of the ECS, and endogenous or endocannabinoids, such as anandamide (arachidonoyl ethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG) that are produced by the body.

Cannabinoid Receptors

Cannabinoids act on cannabinoid receptors located on neurons in the central and peripheral nervous systems and also act on immune and other nonneural cells located in the brain, spinal cord, and periphery. The CB1 receptor was discovered in 1988 and is expressed mostly in the brain and is also found on presynaptic terminals of peripheral nociceptors, and neurons in the dorsal root ganglion and spinal cord. It is classified as an inhibitory G-protein coupled receptor and functions via the regulation of adenylate cyclase and mitogen-active protein kinase (MAPK) signaling pathways. Presynaptic CB1 receptor activation results in the inhibition of calcium influx and the decreased release of the primary neurotransmitter, thereby reducing and/or modulating nociceptive transmission.

The typical neurotransmitters affected are GABA and glutamate; however, acetylcholine, norepinephrine, dopamine, 5-HT and others have been implicated. CB1 receptor activity at the spinal level is postulated to modulate ascending pathways of the spinal thalamic tract, and to suppress nociception, windup, and central sensitization in the spinal cord dorsal horn. At the supra-spinal level, CB1 receptor activity regulates pain through the activation of descending inhibitory pathways in the periaqueductal gray and raphe nucleus, and by acting on the limbic system to modulate the integration of the affective component of pain.

 

Inhaled Cannabis – Does it reduce pain?

A small number of randomized controlled trials (RCTs) performed in the mid to late 2000s evaluated the effectiveness of inhaled cannabis for treating neuropathic pain and generally yielded favourable results. In 2007, a prospective, randomized placebo-controlled trial in 50 patients demonstrated efficacy of smoked cannabis cigarettes for reducing chronic neuropathic pain from HIV-associated peripheral neuropathy. Cannabis cigarettes containing 3.56% THC were smoked three times daily for 5 days, and patients reported a 34% reduction in daily pain, with 52% of patients reporting > 30% reduction in pain, which is the generally accepted minimum pain reduction to be considered clinically significant in studies.

These results were substantiated in 2009 in a phase II, double-blinded, placebo-controlled, crossover trial of analgesia with smoked cannabis in patients with HIV associated distal sensory predominant polyneuropathy. Twenty-eight patients completed the trial and reported significant reduction of pain intensity with cannabis of various potency (1–8% THC), with 46% of patients reporting > 30% reduction in pain vs 18% for placebo. In a study evaluating the efficacy of cannabis for central and peripheral neuropathic pain, 38 patients smoked placebo, 3.5% or 7% THC in 3, 6-h sessions. Both doses of cannabis demonstrated equianalgesia and superiority over placebo. Other researchers studied the efficacy of cannabis smoked short-term in a randomized placebo-controlled trial involving 21 Canadian patients with greater than 3 months of post-traumatic or postsurgical neuropathic pain. They demonstrated significantly lower mean daily pain intensity scores and improved sleep in the high dose (9.4%) cannabis treatment group over placebo. Although these studies primarily evaluated the short-term use of the medical cannabis, the investigators generally concluded that inhaled cannabis was well tolerated with mild to moderate adverse effects.

 

Spinal adjustments – Can the chiropractor help?

The lifetime prevalence of low back pain in the United States may be as high as 84%. The prevalence of chronic low back pain is about 23%; it disables 11–12% of the population. A 13-recent systematic review of the clinical course of non-specific low back pain found that in the first 3 months, 33% of patients showed recovery, but 1 year after onset, 65% still reported pain. The severity, length, or duration of pain for any one individual varies, and the transition from acute to chronic low back pain is difficult to determine.

Pain management approaches vary greatly. Many physicians rely on non-steroidal anti-inflammatory drugs, opioid, and neurotropic medications, or steroid injections and surgery as their main tools. Because of the potential or apparent risks associated with these tools, non-pharmacological approaches, thought to involve minimal adverse events, have become popular.

In recent years, multiple studies have explored the evidence for treating chronic low back pain options include spinal manipulation therapy, behavioural therapy, exercise therapy, transcutaneous electrical nerve stimulation, interferential currents, low-level laser therapy, and yoga. Other 3 therapies include massage, acupuncture, and superficial heat therapy (e.g., therma heat wraps, hot water bottles, heated packs filled with grain, hot towels, and electric heating pads). Manual modalities such as physiotherapy, massage, chiropractic, occupational, and osteopathic therapies, including spinal manipulation and mobilization, are often used together as well as alone to treat chronic non-specific low back pain.

 

How does manipulation compare to other ‘standard’ treatments?

Mobilization and manipulation appear to be safe, based on what was reported in the literature. A small-moderate effect was found in favour of manipulation for patients with chronic low back pain with pain duration of at least 3 months or more. This effect seems to increase over time at 3 and 6 months follow-up for reducing pain compared to other active comparators, namely exercise and physical therapy comparators. Manipulation was also shown to reduce disability.

Thus, getting adjustments for lower back pain was superior to standard treatments.

 

Capsaicin

TRPV1 is a nonselective cation channel that may be activated by a wide variety of exogenous and endogenous physical and chemical stimuli. The best-known activators of TRPV1 are: temperature greater than 43 °C (109 °F); acidic conditions; capsaicin, the irritating compound in hot chili peppers; and allyl isothiocyanate, the pungent compound in mustard and wasabi. Upon prolonged exposure to capsaicin, TRPV1 activity decreases, a phenomenon called ‘desensitization’.

 

Does Capsaicin reduce pain?

Application of high-concentration topical capsaicin, acting on C fibres that supply the pain area, would lead to a reduction in peripheral and central sensitization and subsequent attenuation of DMA. Capsaicin is a potent, highly selective vanilloid receptor subtype 1 (TRPV1) agonist that causes depolarization of the neurons, inducing a short-lived warming sensation, followed by complete defunctionalization.

The efficacy and tolerability of the capsaicin 8% patch (or topical application of capsaicin) has been confirmed in Dynamic Mechanical Allodynia (DMA) (a typical symptom of neuropathic pain (NP)), painful human immunodeficiency virus (HIV)-associated neuropathies, and more recently in painful diabetic peripheral neuropathy.

Clinical trials specifically investigating the treatment of evoked pain are sparse and currently there are no defined standard of care treatments for DMA. Pregabalin is a well-established and widely used treatment medical drug for the treatment of NP, which has been shown to reduce allodynia in experimental studies and was significantly better than placebo in alleviating DMA in patients with PHN. Whilst these studies have demonstrated the clinical benefit of pregabalin in allodynia, including a correlation between changes in the intensity of DMA and overall pain, the relationship between changes in the area of allodynia and a clinical response remains to be explored.

In the recently completed ELEVATE study, the capsaicin 8% patch demonstrated noninferior pain relief versus an optimized dose of pregabalin over 8 weeks (primary endpoint), with a faster onset of action, fewer systemic side effects and greater patient satisfaction with treatment. Not bad eh! Consider our Capzea for nerve pain.

Sciatica – Can Acupuncture Help?

Sciatica is characterized by sciatic nerve pain (pain that radiates from the low back to below the knee), paresthesia (mostly numbness and tingling), and muscle weakness in the affected leg or foot. These symptoms can lead to motor disabilities and mental disorders such as depression and anxiety. The prevalence of sciatica ranges from 1.2% to 43%. The most common cause of sciatica is herniation of the nucleus pulposus. Indeed, about 90% of sciatica cases are due to a herniated disc involving nerve root compression. Other possible causes include a narrow lumbar canal, foraminal stenosis, tumours, and cysts. Herniated lumbar disc-related sciatica is one of the most common conditions managed in primary medical care and a significant cause of absence from work and early retirement. Patients, families, and the society at large all carry part of the burden.

Acupuncture and electroacupuncture (EA) have been applied for the treatment of sciatica since the early 1990s but results of studies on their efficacy have been inconsistent. According to the theory of Traditional Chinese Medicine (TCM), acupuncture needles are inserted into the body, and sufficient manual needling manipulation (e.g., lifting-thrusting and twisting-rotating) of the inserted needles elicits a composite of sensations (the response of the characteristic needle-manipulation sensation is termed deqi, which generally manifests as numbness, heaviness, distention, and soreness), which is believed to be an indispensable component in achieving a therapeutic effect. Fear of needle-manipulation sensation is an important reason as to why patients choose to forego acupuncture treatment.

There is considerable evidence to show that acupuncture treatment produces pain relief for durations that outlast the period of stimulation. These prolonged effects after cessation of acupuncture stimulation may undergo 2 phases: (1) sudden, dramatic relief of pain for several hours after stimulation, and (2) gradual pain relief that returns days or weeks after a single treatment session. In a recent study, we will observe the duration of pain relief to provide information as to how long pain relief lasts after a single session of AA.

 

The take home message

Pain affects everyone. And I get the whole ‘pain killer’ idea. I mean, who would not what their pain ‘killed’. After all, pain is a (well) pain! If all you need to do is pop a pill and the pain goes away, then why not do it?

Obviously, there are good reasons to avoid the opioids. There are also good reasons to take them short term. For example, recovering from painful surgery, pain killers for a few days may be a good idea. However; what if you have a bad back? That can go on for months or even years. Also, opioids or any other pain killers don’t address the cause of the condition. If your back is ‘out’, opioids don’t put your back ‘in’. The take-home message is if you are going to take the pain killers, take them sparingly and with close consultation with your doctor.

Explore the less harmful pain options first but always try to address the cause of your pain firstly.

 

 References

Gemayel Lee & Brittany Grovey & Tim Furnish & Mark Wallace. Medical Cannabis for Neuropathic Pain. Current Pain and Headache Reports (2018) 22:8

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Richard deShazo, McKenzie Johnson, Ike Eriator, Kathryn Rodenmeyer, Backstories on the U.S. Opioid Epidemic Good Intentions Gone Bad, an Industry Gone Rogue and Watch Dogs Gone to Sleep, The American Journal of Medicine (2018)

Gemayel Lee & Brittany Grovey & Tim Furnish & Mark Wallace. Medical Cannabis for Neuropathic Pain. Current Pain and Headache Reports (2018) 22:8

Gemayel Lee & Brittany Grovey & Tim Furnish & Mark Wallace. Medical Cannabis for Neuropathic Pain. Current Pain and Headache Reports (2018) 22:8

Gemayel Lee & Brittany Grovey & Tim Furnish & Mark Wallace. Medical Cannabis for Neuropathic Pain. Current Pain and Headache Reports (2018) 22:8

Gemayel Lee & Brittany Grovey & Tim Furnish & Mark Wallace. Medical Cannabis for Neuropathic Pain. Current Pain and Headache Reports (2018) 22:8

Manipulation and mobilization for treating chronic low back pain: a systematic review and meta-analysis. Coulter ID, Crawford C, Hurwitz EL, Vernon H, Khorsan R, Suttorp Booth M, Herman PM. Spine J. 2018 Jan 31. pii: S1529-9430(18)30016-0

G. Cruccu, T.J. Nurmikko, E. Ernault, F.K. Riaz, W.T. McBride, M. Haanpa. Superiority of capsaicin 8% patch versus oral pregabalin on dynamic mechanical allodynia in patients with peripheral neuropathic pain. European Journal of Pain. 31 October 2017

G. Cruccu, T.J. Nurmikko, E. Ernault, F.K. Riaz, W.T. McBride, M. Haanpa. Superiority of capsaicin 8% patch versus oral pregabalin on dynamic mechanical allodynia in patients with peripheral neuropathic pain. European Journal of Pain. 31 October 2017

G. Cruccu, T.J. Nurmikko, E. Ernault, F.K. Riaz, W.T. McBride, M. Haanpa. Superiority of capsaicin 8% patch versus oral pregabalin on dynamic mechanical allodynia in patients with peripheral neuropathic pain. European Journal of Pain. 31 October 2017

Anfeng Xiang, MD,a Mingshu Xu, PhD,b Yan Liang, PhD,b Jinzi Wei, PhD,a and Sheng Liu, PhDa, Immediate relief of herniated lumbar disc-related sciatica by ankle acupuncture

A study protocol for a randomized controlled clinical trial Medicine (Baltimore). 2017 Dec; 96(51): e9191.

Anfeng Xiang, MD,a Mingshu Xu, PhD,b Yan Liang, PhD,b Jinzi Wei, PhD,a and Sheng Liu, PhDa, Immediate relief of herniated lumbar disc-related sciatica by ankle acupuncture

A study protocol for a randomized controlled clinical trial Medicine (Baltimore). 2017 Dec; 96(51): e9191.