Cancer Pain

Cancer pain can have numerous causes. As tumors grow, they can compress or put pressure on nearby nerves, the spine, organs, muscles, bones, and other tissue structures causing pain. Tumors can likewise erode tissue throughout the body, causing nerve, organ, or bone damage that leads to neuropathic pain, much like peripheral neuropathy from shingles or diabetes. Peripheral neuropathy can also be caused by cancer treatment; many types of chemotherapy can lead to peripheral nerve damage causing neuropathic pain. Some researchers are investigating how psychedelics like psilocybin can improve pain from chemotherapy-induced peripheral neuropathy and how LSD can improve cancer-induced bone pain. (Prof. Imad Damaj & Stephen Ross, see links below).

Additionally the tumor growth cycle can release pain-promoting chemicals, which can in turn upregulate pain sensation throughout the nervous system, leading to peripheral and central sensitization. Peripheral and central sensitization may also develop due to various operations to combat cancer, with the removal of organs, tissue, bones, or limbs leading to phantom-pain. As an example, mastectomies can lead to phantom-breast pain, and hysterectomies can cause phantom-uterine cramping and other kinds of secondary neuropathic pain leading to central sensitization.

Psychedelics have a strong track record when being researched for cancer pain, beginning with the Kast study in 1964, so we should expect strong growth in this area of investigation and treatment.

Neuropathic Pain

Neuropathic pain is due to disease, dysfunction or injury to the nerve tissue itself (e.g. peripheral diabetic neuropathy, chemo induced neuropathy, small fiber neuralgia in persistent Lyme, etc) and can be both peripherally or centrally generated.. Often characterized by sensations of burning, tingling, electric shocks, pin & needles, cold & touch hypersensitivity, neuropathic pain is generated by three main mechanisms: central sensitization, ectopic foci, and ephaptic transmission. 

With neuropathic pain, the brain cannot properly sense or “map” an area of the  body and thereby generates the “alarm signal” of pain  as a protective mechanism for this loss of sensing ability. This alarm signal then persists inappropriately, keeping the individual in chronic pain and debilitation. 

Classic serotonergic psychedelics have several mechanisms for reducing neuropathic pain, including cortical reorganization, normalization of inflammation, activation of 5HT2a receptors past site of injury, and regulation of BDNF. 

Phantom / Phantom-Limb Pain

Somewhere between 50-85% of all limb-loss survivors will experience some level of phantom pain as a mixture of peripheral sensitization from the residual limb and central sensitization. Phantom limb pain is felt in missing limb and occurs through a process called deafferentation, where the loss of signal from ascending or afferent nerve inputs register as a severe alarm to the CNS. That alarm signal generates intense pain or odd sensation and many with limb-loss get “stuck” in this state.

Several studies have shown that psychedelics create profound cortical reorganization, allowing brain networks to resume healthy normal defaults that reconcile new body configurations and in this way, have been shown to lessen PLP.

Headache & Head Pain

The pioneering research done at Yale University established proof of concept that psychedelics could be effective for pain conditions, provided evidence of direct mechanisms of action in creating significant analgesic, anti-nociceptive, and prophylactic response.

The review studies, data troves, & dosing protocols that arose out of the cluster headache communities and leading patient advocacy groups like Clusterbusters have been imperative to development of trials & treatment.

Fibromyalgia

With a global prevalence of 2-8% (affecting mostly women) and poor treatment outcomes, the need for alternative approaches to this poorly understood disorder is great. Fibromyalgia has significant overlap with many other diagnoses, including chronic fatigue, Lyme disease, Multiple Sclerosis, and Lupus. Fibro is likewise often comorbid with conditions of central sensitization (e.g. pelvic pain, TMJ, migraine, IBS), and chronic back pain. Imperial College London’s Centre for Psychedelic Research is currently running a trial looking at the efficacy of psilocybin therapy for the treatment of Fibromyalgia pain.

Pain Comorbid w/PTSD

Using exploratory data from participants who completed chronic pain measures in the MAPS Phase II open-label trial, using MDMA-AT to treat PTSD, Dr. Devon Christie and Pamela Kryskow. M.D. found a high comorbidity of chronic pain with PTSD. Upon completion of analysis, their team found, “that chronic pain scores among medium and high pain subgroups were significantly lower following MDMA-AT.” This preliminary data gives an intriguing look into how MDMA and MDMA-AT may be used to modulate pain as it occurs alongside PTSD. The team is currently preparing for further study.

Infection-Associated Chronic Illness (IACI)

While the pathogenesis between infection and persistent symptoms remains largely unknown, Infection-Associated Chronic Illnesses (IACI) (e.g. Chronic Fatigue syndrome, persistent Lyme, Epstein-Barr, and Long-COVID) share common symptoms including prolonged fatigue, brain-fog, non-specific pain, gastrointestinal issues, and chronic inflammation. Preliminary studies show the potential of psychedelics to bring inflammation back to a healthy baseline, which may be supportive of patients’ recovery and a reduciton in suffering.

Interest in using these medicines as part of IACI treatment protocols is rapidly growing. Look to the PPA course for compelling case studies and resources.

Central Sensitization

Central sensitization is a condition in which the central nervous system (CNS) becomes more sensitive to pain (nociceptive) signals from nerve cells. This can happen for a number of reasons, including chronic pain, injury, or stress. When the CNS is more sensitive to pain signals, people may experience more pain than would be expected from the severity of their injury or condition. They may also be more sensitive to other types of stimuli, such as touch, light, and noise. Central sensitization is thought to be involved in other chronic pain conditions, such as fibromyalgia, TMJ, pelvic pain, chronic fatigue syndrome, IBS, migraine, and complex regional pain syndrome (CRPS). 

Through activation of the 5HT2a receptor, it is hypothesized that classic psychedelics may support pain relief in conditions of central sensitization by augmenting pain pathways, inflammation, and through the “resetting” of entrenched pathways of belief and neural response, generating a window of plasticity for positive reframing of the individuals lived experience of pain. See link below for the PsiloPain trial on Fibromyalgia, currently happening at Imperial College London.

Low Back Pain

About 9/10 people who seek treatment for low back pain cannot be diagnosed with a specific cause. While most cases of low back pain go away on their own within 6-12 weeks, some people develop chronic pain. While some low back pain is certainly biomechanical in nature, much of that which cannot be attributed to a specific cause is likely due to a condition called central sensitization. Central sensitization represents a change in the way the nervous system processes pain signals, becoming hypersensitive, generating inappropriate pain. Through complex mechanisms we have learned that the low back is predisposed to feeling pain, many visceral and truck related pain gets referred to this area, making it a prime location for the development of central sensitization.

The Heifets Lab at Stanford, in collaboration with UCSF, is initiating a clinical trial into the potential of psilocybin to reduce non-specific low back pain. The results of this study will shed light on not only low back pain, but likely on how classic psychedelics may support the reduction in pain for similar pain conditions and other conditions of central sensitization.

Inflammatory Pain & Autoimmunity

Recent studies in animal models have shown the remarkable potential of psychedelic medicines to normalize body-wide levels of inflammation and to modulate the immune response, thereby lessening inflammatory pain and autoimmune reactivity. 

Through the lowering of inflammatory cytokines (e.g. TNF-a, IL-1b, and IL-6), the upregulation of anti-inflammatory cytokines (e.g. IL-10), and the modulation of the psychological stress response, several psychedelic compounds may prove to be more powerful at regulating inflammation than existing pharmaceuticals. Look to the PPA coursework for lectures on this burgeoning research from Charles Nichols and Natasha Mason. 

Spinal Cord Injury

Spinal cord injury pain occurs as a result of damage to the spinal cord. This damage can be caused by a trauma, such as a car accident or fall, or by a disease, such as multiple sclerosis.

Spinal cord injury pain can be a complex and challenging condition. It can affect any part of the body, and it can be described in many different ways, such as burning, aching, throbbing, or shooting.

Evidence from case studies suggests that psychedelics are likely improving and resolving pain in SCI survivors in a similar fashion to patients with phantom-limb pain and peripheral neuropathy, but on a more global scale due to the widespread impacts of spinal cord injury. Loss of afferent nerve signals which ascend up the spine to the CNS, is a cause for alarm in the CNS, often resulting in pain that becomes chronic with time, causing an entrenchment of that pain output in the CNS.

Psychedelics create profound cortical reorganization, allowing the brain to create sensory remapping, and potentially reestablish lost or atrophied neural connection via neuroplasticity. Descending inhibition, reductions in inflammation, and potential improvements in autonomic responses via changes in gene expression and stress resilience are also likely candidates that contribute.

Complex Regional Pain Syndrome (CRPS)

Complex regional pain syndrome (CRPS) is a chronic pain condition whose cause is not fully understood. It is thought to be caused by a malfunction of the nervous system in the aftermath of an injury. CRPS affects the nerves, blood vessels, and skin, usually developing in a limb after an injury, such as a fracture or sprain. It can occur after surgery or even a minor injury, such as a blood draw. CRPS is regional, meaning that it affects a large, specific area of the body, such as an entire arm or leg, rather than following a dermatomal distribution (the area of skin supplied by a single nerve root). CRPS causes a variety of symptoms, including:

• • Severe pain that is often described as burning, throbbing, or crushing
  • Swelling
  • Changes in skin color and temperature
  • Increased sweating
  • Decreased range of motion
  • Sensitivity to touch
  • Muscular atrophy

Many of the above symptoms seem to be due to autonomic nervous system dysregulation, the part of the nervous system that controls involuntary bodily functions, such as heart rate, blood pressure, and digestion. CRPS is designated as an “orphan” condition, meaning there are no pharmaceutical drugs that have been proposed to treat it, given its rarity and difficulty to improve symptoms. Several anecdotal reports from CRPS patients show the potential of psychedelic medicines to support those suffering from this chronic condition.