Integrative management of chronic pain

Integrative Chronic pain summary

The following are my own notes on chronic non-cancer pain derived from extensive reading of the medical literature and my own experiences treating chronic pain patients. As with all posts on this web site, for general education only and does not constitute medical advice to either patients or practitioners. 

1. Introduction
   1. In the US, chronic pain affects over 116 million people, more than the total affected by cardiovascular disease, diabetes and cancer combined.
   1. Acute pain serves us well as a warning sign of danger and potential (or actual) tissue damage. 
   1. Chronic pain has the vague definition of pain that has persisted beyond the time of healing. Chronic pain is often a maladaptive expression of learned hypervigilance: fear of pain leads to feed-forward loop generating more pain, culminating in self-sustaining central sensitization that can be difficult for the patient to escape.
   1. The biggest predictor of chronic pain is the emotional charge – high risk if depressed, anxious, past trauma. Can highly predict who will have chronic low back pain (CLBP) based on psychosocial factors.
   1. Stress-Appraisal-Coping Model: 
      1. We are wired for negativity bias as a survival mechanism, amplifying negative experiences.
      1. Negative appraisals of threat and loss lead to hypervigilance, fear and eventually depression.
      1.  Avoidance leads to deconditioning with less musculoskeletal adaptive capacity and increased irritability.
   1. Chronic pain becomes a disease in itself.
   1. Very isolating, with familial, vocational, social, and community disruption as well as adverse effects from the long-term use of analgesics, especially NSAIDs and opioids. 
   1. Stress, hopelessness, fatigue, depression, anxiety, decreased concentration, and sleep disturbances and chronic pain feed on each other.
   1. Even with the brain’s intrinsic negativity bias, with directed mindful attention, the brain can be rewired for positive valences such as joy and safety. Meditation, mindfulness and hypnosis, Tai chi — all of these types of therapies create neurologic fitness, just as physical exercise creates physical and cardiovascular system fitness. The neurological remodeling occurs because of will and focused attention, which need to be sustained and consistent.
   1. Chronic stress may fatigue adrenals, depressing cortisol and no longer suppressing inflammatory mediators. Chronic stress selectively increases the number and activation of microglia in certain stress-sensitive brain regions, which may play a role in visceral hyperalgesia.
   1. Only 36% of the population reports no Adverse Childhood Experiences (ACEs). Rates of self-reported histories of emotional, sexual, and physical abuse are 10.6 %, 20.7% and 28.3% respectively.
   1. The interconnectedness of the pain processing regions along with their affective and cognitive regions are more like an orchestra — the instruments are the same but what music they make together depends on:
      1. The composer (individual history and genetics)
      1. The musicians (physiology and health)
      1. The conductor (individual interpretation)
   1. Brain areas involved in pain and in mind-body integration practices such as meditation have strong overlap.
   1. Patients vary considerably in their self-efficacy and patients reporting higher levels of self-efficacy have lower levels of pain and lower levels of psychological distress and more positive medical outcomes.
   1. Improvements in self-efficacy are related to positive short- and long-term outcomes of pain coping skills training and educational self-help interventions. Integrative medicine offers a vast menu of arenas for supporting self-efficacy from mind-body approaches, to nutrition, to various exercises and ways of engaging conventional and alternative medicine systems.
   1. The challenge for the practitioner is to dismantle the fear of pain that keeps sufferers from pursuing therapies, and to ignite the patients’ trust in their intrinsic health that can be used to regain some quality of life. Hope needs to be rekindled, as the most important outcome of the early appointments. Then the engagement of the patient’s internal healing potential will provide the power for healing. After all, there is much health in a person, even if s/he is in pain.
   1. The goal is to remove obstacles to regaining health and to harness and support the unfathomable power of the body, mind, heart and spirit to heal.
2. Non-pharmacologic treatment of chronic pain: Fortunately, there are many effective interventions: Stress & inflammation may be treated using mind-body, nutritional, and botanical modalities. Anatomic malalignment as a result of altered biomechanics (from trauma, compensation, overuse or deconditioning) may, over time, lead to physiologic dysfunction, including edema and inflammation. This somatic dysfunction may be treated using both exercise and manipulation.
   1. Reframing of painful stimuli allow patients to unlearn, manage, and even heal from chronic rheumatologic pain syndromes. Chronic pain is mainly central sensitization, though peripheral sensitization can also contribute to chronic pain. HURT DOES NOT NECESSARILY EQUAL HARM. Central sensitization means pain felt in the tissues is no longer being (primarily) generated by the tissues. Because the tissues are no longer the issue, it is not helpful for patients to seek a greater understanding of the diagnostic label they may have been given—like a patient learning all he or she can about fibromyalgia. Rather, it is more important for patients to gain an understanding of the presentation of their particular symptoms. Let go of trying to forcibly control pain: the more a patient expects and comes to hate his or her pain, the more he or she unwittingly participates in its continuance. Teach a pain patient to stop hating their pain, which includes wishing that it would go away. A full understanding of central sensitivity is thus a first step in reducing fear so that healthful movement strategies may be adopted. Mindful use of language – has powerful influence in both positive and inadvertent negative clinical outcomes.
   1. Specific modalities with efficacy supported by research:
      1. Mindfulness-Oriented Recovery Enhancement (MORE) 
         1. Combines Cognitive beharioral therapy (CBT), Mindfulness and positive psychology. MORE led to significant reductions in pain severity (P = .014) and pain-related functional interference (P = .002) that were maintained for 3 months following the end of the treatment groups. Although the magnitude of changes in pain severity was modest, participation in MORE reduced the impact of pain on daily functioning by nearly one quarter from pretreatment levels of impairment. Journal of Pain & Palliative Care Pharmacotherapy. 2014; 28:122 –129. DOI: 10.3109/15360288.2014.911791
      1. Biofeedback: effective for tension & migraine headache, muscular neck & back pain, chronic pelvic pain, proctalgia, neuropathic pain. 
         1. Headache: QEEG biofeedback or computer animated relaxation biofeedback
            1. SS anemia in children – biofeedback assisted relaxation
      1. Clinical hypnosis Patient can be taught self-hypnosis to support self-efficacy. (See: The Role of Suggestions in Hypnosis for Chronic Pain: A Review of the Literature. The open pain journal 3(1):39-51 2010 Dillworth T, Jensen MP; PMID: 21686037). Effective for many conditions, including:
         1. LBP, arthritis, TMJ, fibromyalgia
         1. Cancer pain, sickle cell disease
         1. Anticipatory anxiety during painful medical procedures, with anesthesia & surgery. 
         1. IBS: Gut-directed hypnotherapy 
      1. Guided imagery– often combined with other modalities.
         1. Pediatric chronic functional abdominal pain
         1. Can add music, Progressive muscular relaxation (PMR). Effective for cancer pain, others.
      1. Mindfulness based Stress reduction (MBSR) effective in wide variety of pain syndromes, including breast cancer pain, fibromyalgia
      1. Yoga shown effective for labor pain, cancer, functional abdominal pains, others
   1.  Somatic dysfunction treatment: crucial component of integrative pain management. Body has incredible ability to compensate for trauma, both physical and emotional, splints around the injured areas, often even after acute injury has healed. Adhesions inhibit normally fluid tissues from freely sliding over one another, creates layers of abnormal biomechanics, until finally, sometimes years later, the end of the body’s ability to compensate may be reached and pain results. Cells sense and respond to mechanical stress via mechanotransduction.  Biomechanical dysfunction may possibly lead to less-than-optimal cellular function. Correcting biomechanics can have far-reaching beneficial effects, including decreased pain, better postural alignment, improved autonomic function and tissue perfusion.
      1. Neuromuscular Medicine (NMM)
         1. Effective for LBP, headache (including migraine), Irritable bowel syndrome (IBS) and may be more cost-effective than allopathic tx.
      1. Chiropractic
         1. Effective LBP, headache
      1. Massage– may be relaxation or structural type, e.g. weekly
         1. Effective for LBP, knee osteoarthritis (OA)
         1. Small studies suggest efficacy for various chronic pelviperineal pains (such as vulvadynia and dyspareunia)
      1. Meditative movement therapies (MMT) of tai chi, qi gong and yoga
         1. Effective for fibromyalgia
         1. Helpful for various pain syndromes, e.g. back pain, rheumatoid arthritis, headaches/ migraine and other pain
         1. Prevention: yoga instructors have significantly less degenerative disc disease than the matched control group
         1. Tai Chi effective for LBP, possibly knee OA.
      1. Feldenkrais & Alexander technique
         1. Effective for LBP, neck, shoulder pain
      1. Acupuncture– attempts to correct blocked or deficient bioenergy or ‘chi’
         1. Much safer than many conventional pain treatments, such as NSAIDs.
         1. Difficult to study scientifically. Traditional empiric evidence of efficacy
      1. Physical Medicine and Rehabilitation (PM&R) – focuses on function
   1. Graded and progressive exposure to movement and exercise: ‘Movement is the medicine’. Healing from almost any physical pain syndrome is facilitated by movement (of course done carefully and appropriately). Reconditioning requires thoughtful planning and consistent, appropriate and skillful execution. Functional fitness evaluation & goal setting. Assess hobbies and leisure activities. Functionally specific movements and exercises are top priority, broken down into graded, stepwise progressions. Simplified example: walking before running Assess irritability:  low – able to withstand significant movement and exercise without a flare-up. High irritability – flares with only minimal movement or exercise. Progression plan: Once baseline fitness and irritability level established, plan the progression of the movement/exercise program. This involves juggling the variables of time, volume and intensity. Progress time first. If highly deconditioned & irritable patient, start with very low volume and intensity movements.  Example – patient with OA can sit and spin on a stationary bike for 5 minutes without flaring-up, plan to increase the time spent riding by 15 to 30 seconds per day. In a very short time your patient can be riding comfortably for a half hour or more, thus achieving his or her goals for increasing tissue fitness and pain reduction. Next increase repetitions (reps). Lastly increase intensity, e.g. weight or load. When increasing load, lower the repetitions of the exercise. Goal: Generally a rheumatologic patient can find a balance between these three variables that allows for 30 minutes of exercise per day, 3 to 5 times per week. Such a program should help with pain reduction while increasing their tissue fitness. 
   1. Healthy attitude towards pain during rehab: 
      1. Patience: in early stages of recovery even light movement or exercise is often painful, and therefore misunderstood by the patient as harmful. To that extent, the patient’s sensitized nervous system sets pain thresholds very low and does not accurately sense actual threats to tissue damage. 
      1. Pain spread is just a false signal: there are no segregated parts of the nervous system, so more and more of the neural network may begin to participate in a persistent pain experience. As a result, the patient may feel as if the pain is spreading to other body parts. Knowing this is very helpful in reducing fear, catastrophizing and hypervigilance. 
      1. Pain may worsen but still safe: a sensitized nervous system then is merely increasing its warning in a misguided effort to stay safe. It is often helpful to teach a patient to talk to his or her nervous system, saying things like “thanks for the warning, but I’m okay.” This is a primary form of reframing pain signals. 
      1. Accept pain unpredictability – due to the myriad ways thoughts, emotions and activities sum to create pain experiences. Don’t spend too much energy puzzling out the exact reasons why the pain is high on a given day. Often, there is no explicit explanation accessible to rational thought and they may draw false conclusions that end up further restricting their activity and worsening the pain. Teach them to allow the pain to arise and pass without strong emotion. Rather than feeling compelled to figure it out or heal it in the moment, learn to manage reactions to it. Over time, as one’s emotional reactivity decreases, so too will one’s overall sensitivity, and thus the unpredictability of the pain. Support from a physical therapist (PT) (or certified strength and conditioning coach) who understands pain from both the tissue and emotional perspectives is critical to guide pain patient through progressive movement and exercise. Cognitive behavioral therapy (CBT) to assist in reframing and emotional support. Social support: warmth, touch and positive social interactions activate oxytocin release. This hormone may have an anti-stress effect and increase pain threshold. Positive effects of social interactions also include lower levels of inflammatory cytokines and lowered stress reactivity.
   1. GI health & Nutrition. Normalizing GI function is essential in treating chronic pain. Often the pain patient is so fatigued or physically or emotionally limited that nutrition is less than optimal, with convenience foods that may have high glycemic index, be pro-inflammatory or nutrient poor as the primary source of food. Doing a thorough intake, diet history, and addressing nutrition with these patients is vital.
      1. GI Disrupting factors to address include stress, poor diet, antibiotics, corticosteroids, infections & parasites, food intolerances and allergies
      1. Stress from any cause, such as excess life demands, early abuse or chronic pain, can dramatically change the gastrointestinal environment, altering microbiota which are necessary for stressor-induced increases in circulating cytokines. Altered GI function may predispose to anxiety.
      1. Lipopolysaccharide found in the outer membrane of Gram-negative bacteria is a potent stimulator of immune (and therefore inflammatory) responses. The imbalance of gram negative bacteria has been linked to hyperalgesia as well as to sensitization of trigeminal sensory neurons
      1. Beneficial bacteria can displace potentially pathogenic bacteria, influence nutrient and vitamin production, help remove toxins and stimulate the gut associated lymphoid tissue (GALT).
      1. Correct dysbiosis of the gut microbiome in chronic pain patients, for example with a plant predominant whole foods diet and cultured foods (yoghurt, kefir, miso, etc.). At this time this remains a conceptually derived approach – clinical trials proving efficacy are not yet available.
   1. Encourage all chronic pain patients to quit tobacco use (smoking, vaping, chewing). Smokers have increased pain, worse function and increased risk of abusing prescribed opioids.
   1. Optimize ‘pillars of health’ – healthy eating, sleeping, exercise, stress management, relationships, spirituality in all chronic pain patients
   1. ‘Diabesity’ (visceral obesity and insulin resistance syndromes such as DM2) is associated with chronic pain, multiple aggravating comorbidities such as sleep apnea, depression, cognitive impairment, OA, CVD, etc.  A plant-predominant (at least ½ plate veggies of different colors) whole foods eating pattern and regular exercise are important in all chronic pain patients, but especially in these patients.
3. Botanicals & supplements with at least preliminary research supporting efficacy in pain syndromes. Use these only under the guidance of a properly trained health care practitioner and please review proper use and cautions on all these from standard references such as Integrative medicine textbooks, Natural Medicine database, etc.):
   1. 5-hydroxytryptophan (5-HTP):
      1. Fibromyalgia & insomnia
      1.  Chronic headache
      1. Typical dose: 100 mg po TID or 300 mg qHS
   1. Ashwagandha (with other botanicals such as ginger, turmeric, boswellia): OA, RA.
      1. Typical dose of powdered root is 2-3 grams per day, or equivalent in tincture form. There are standardized extracts available containing 2.5% withanolides and taken at a dose of 500 mg 2-3 X/day
   1. Avocado soybean unsaponifiables (ASU) 1/3 avocado, 2/3 soybean oil ASU contains various compounds, including phytosterols, β-sterols, stigasterol and campestrol, and it may improve articular collagen synthesis while also serving as an anti-inflammatory.
      1. 3 studies show efficacy of ASU for knee and/or hip OA with less pain and swelling after 3-6 months of 300-600 milligrams of ASU daily, using the proprietary formula Piascledine®300. SEs seem rare, possible rash, GI upset, LFTs (causality unclear).
   1. Boswellia serata– inhibits the synthesis of the pro-inflammatory enzyme, 5-lipoxygenase, improves OA sx. Research supported brands:
      1. 5-Loxin®, 100-250 milligrams daily
      1. Alfapin® 50 mg BID
      1. Boswellia extract 333 milligrams three times daily
      1. SEs low
   1.  Butterbur (Petasites hybridus) – natural anti-histamine for allergic rhinitis and for migraine headache prophylaxis. Its use in migraines is likely due to smooth muscle relaxation and leukotriene inhibition
      1. a standardized butterbur extract (Petadolex®) 50-75 milligrams BID decreases # migraine attacks/month and decreased med use.
      1. CAUTION: A standardized extract (e.g. Petadolex) free of the hepatotoxic pyrrolizidine alkaloids must be used; whole plant butterbur should not be ingested.
   1. Cat’s claw (U. tomentosa and U. guianensis)
      1. Arthritis
         1. RA: Krallendorn (U. tomentosa root extract brand) 20 mg po TID decreased joint pain in DBRCT. Krallendorn is a patented brand name of IMMODAL Pharmaka GmbH and refers exclusively to the preparation containing a standardized extract from the root of the pentacyclic chemotype of Uncaria tomentosa.
         1. OA: freeze-dried preparation of U. guianensis bark 100 mg po daily
         1. Serious adverse effects are listed but likely rare, include GI upset, kidney failure, neuropathy, altered heartbeats, immunostimulation, hypotension, decreased estrogen and progesterone levels, and increased bleeding
         1. CAUTION: may inhibit the cytochrome P450 CYP3A4 enzyme
   1. Harpagophytum procumbens (Devil’s claw) standardized to 50-100 milligrams harpagoside daily which inhibits various inflammatory mediators via NF-kappa-B and COX-2 inhibition.
      1. Effective in arthritis – should provide 50 – 100 mg harpagosides/d
         1. Harpadol (Arkopharma) 1 – 2 caps (435 mg each) po TID (maximum dose of 2.6 grams/day provides a total of 57 mg of the harpagoside constituent and 87 mg of total iridoid glycosides. Each 435 mg capsule contains 2% harpagoside (9.5 mg per capsule) and 3% total iridoid glycosides (14.5 mg per capsule).
         1. Doloteffin, Ardeypharm) Dose: total of 2400 mg/day providing 60 mg/day of the harpagoside constituent.
      1. Other reputable brands:
         1. Nature’s Way Devil’s Claw: Take 1 tablet (480 mg) 2 -3X/d with food.
      1. Adverse effects mainly minor, GI upset
      1. CAUTION: Devil’s claw may increase stomach acidity, lower blood sugar, and interact with anti-coagulants and digoxin
   1. Feverfew (Tanacetum parthenium)
      1. Migraines: use C02 extract (MIG-99), dosed at 6.25 mg TID
      1. Adverse effects: GI upset
   1. Ginger (Zingiber officinale) rhizome contains numerous compounds that inhibit pro-inflammatory prostaglandins and leukotrienes.  Often combined with other botanicals such as turmeric, boswellia. Modest efficacy alone for:
      1. OA
      1. Dysmenorrhea
      1. Adverse effects uncommon. Mild GI upset.
      1. Extracts typically sold as anti-inflammatories are too potent for use during pregnancy
   1. Glucosamine and chondroitin
      1. Mixed evidence, recent major trial showed no benefit. GAIT trial found insignificant trends for improvement in joint pain with celecoxib 200 milligrams daily and glucosamine hydrochloride 1500 milligrams daily; and very little effect with chondroitin sulfate and the glucosamine-chondroitin combination
      1. Possible Glucosamine sulfate better than the HCl salt.
      1. Bioavailability of Glucosamine sulfate and Chondroitin sulfate may be improved by taking them separately as opposed to as a combination pill (preliminary evidence)
      1. Pharmaceutical grade formulations such as InvigoFlexD (distributed by WynnPharm) may be more efficacious
   1. MSM(Methylsulfoylmethane) is found naturally in veggies & fruits, sulfur moiety may scavenge free radicals, thus decreasing inflammation.
      1. 1 RCT shows less pain in knee OA.
      1. Adverse effects minimal
   1. Magnesium– Deficiency alters neurotransmitter release, hyper-aggregates platelets, vasoconstricts, activates NMDA receptor with resultant glutamate release into the synapse. Mg blocks spreading cortical depression induced by glutamate. Stress reduces Mg availability.
      1. Migraines, especially menstrual migraines: 2 double blind randomized controlled trials (DBRCTs) show 600 mg/d Mg decreased frequency of migraines (1 other trial was negative). Intracellular Mg low in ½ of women with menstrual migraine attacks, even if serum Mg is normal.
      1. Dose typically 600 mg/d, can increase to 1 G/d. Use Mg chelates or Slo-Mg
         1. IV MgSO4 1 gram can terminate migraine with aura or if low ionized Mg
      1. Adverse effects: diarrhea is rate-limiting SE.
      1. CAUTION in poor renal function
   1. Omega 3 fatty acids.  EPA and DHA compete with dietary or n-6-derived arachidonic acid as substrates for metabolism by cyclo-oxygenase and lipoxygenase enzymes. Arachidonic acid leads to the formation of series 2 prostaglandins (PGs), series 4 leukotrienes (LTs), and thromboxane A2, all of which are pro-inflammatory in the human body, while n-3 fatty acids lead to the formation of series 3 PGs, series 5 LTs, and thromboxane A3, which are less inflammatory, probably accounting for the benefits of omega-3s in arthritis
      1. RA – reduces joint inflammation and med use.
      1. Dose: EPA 2 – 4 G, DHA 1-3 G
      1. Adverse effects low. Freeze capsules to lessen fishy burp.
   1. S-adenosylmethionine (SAMe) used in supraphysiologic doses for pain associated with fibromyalgia and osteoarthritis. Broad physiological effects, including centrally-acting changes in neurotransmitter concentrations
      1. Fibromyalgia
      1. OA
      1. Dose for above typically 200 – 600 mg/day
      1. Adverse effects generally mild & self-limiting: GI upset. (Note: higher doses used for depression are contraindicated in bipolar because of concerns might induce mania)
   1. Baikal, or Chinese, skullcap (Scutellaria baicalensis/barbata)
   1. Turmeric (Curcuma longa) contains curcuminoids, one of the principal being curcumin, which has been shown to inhibit numerous inflammatory mediators.
      1. RA – 1200 milligrams of curcumin daily decreases inflammation and improves walking time. In 1 trial 500 mg curcumin po daily improved Disease Activity Score (DAS) more than diclofenac.
      1. OA – propriety curcumin/phosphatidylcholine extract (Meriva, Indena SpA) at doses of 200 mg per day the global WOMAC score decreased by 58% (P<0.05), walking distance in the treadmill test was prolonged from 76 m to 332 m (P<0.05), and CRP levels decreased from 168 ± 18 to 11.3 ± 4.1 mg/L in the subpopulation with high CRP when compared to the control group (Belcaro 2010).
      1. 1 trial turmeric extract (from Curcurma domestica) 500 milligrams of curcuminoids four times daily helped to control knee arthritis pain as well as 400 mg twice daily of ibuprofen
      1. Adverse effects minimal:      GI upset
      1. Note: needs to be complexed with phosphatidylcholine or piperine from black pepper to have adequate bioavailability.
   1. Willow (Salix alba, or white willow) contains several glycosides (salicin, salicortin, fragilin, and tremulacin) and the primarily metabolite, salicylic acid, that act as nonselective COX-1/COX-2 inhibitors
      1. LBP – 120-240 mg salicin daily
      1. Note: Estimates are that 240 milligrams of salicin is equivalent to 50 milligrams of ASA, leading most experts to consider Salix alba as an adjunctive therapy for pain, at best.
      1. Adverse effects: GI distress
   1. Cannabis and derivatives?  Many different cannabinoids, some with relaxant properties. Research is preliminary.
   1. Topicals:
      1. Capsaicin cream or patches.
         1. OA e.g. knees, hands: Modest benefit with creams containing 0.025%- 0.075% capsaicin applied 3-4 times daily – adjunctive tx.
         1. For neuropathic pain, the 0.075% cream helps
         1. PHN: a single, 60-minute application of 8% capsaicin patches (Qutenza) provides up to three months relief from pain associated with post-herpetic neuralgia (PHN).  Can try off label for HIV-related neuropathy and other cases of peripheral neuropathy.
         1. CAUTION: always use gloves when applying. Local cooling or oral analgesics if burning is an issue. Don’t touch eyes, genitals or other sensitive tissues after applying!
4. Other botanical uses
   1. Nervines can help with sleep and anxiety in chronic pain: Valerian, Passionflower, hops, Chamomile
   1. Oral mucositis, lichen planus responds to chamomile
   1. Rhodiola helps fatigue, some mood elevating effects. May be good for fibromyalgia
   1. Migraines– use Petadolex (Butterbur) LOE A & Magnesium
   1. Curcumin at sufficient dose (e.g. 1500 mg/day) has analgesic benefit
5. Pharmacologic: Often as a treatment program begins, immediate pain control is needed to ease suffering and to allow the patient enough relief and free sufficient psychic (emotional) energy to devote him/herself to the usually more labor-intensive integrative approaches. And sometimes, integrative approaches cannot resolve chronic pain completely, so some medication may be needed long term. Below are some brief comments. Please reference standard resources for full information on proper use. 
   1. Acetaminophen: max. officially 4 G/d but in chronically ill such as many pain patients consider max. 3 G/d. Consider adding N-acetylcysteine (NAC) if higher range and liver risk.
   1. NSAIDs: Topical NSAIDs are best when used for acute musculoskeletal pain. Because of the route of administration, there are localized effects and no gastrointestinal concerns. Avoid long term use of systemic NSAIDs as first line chronic tx whenever possible. The main adverse effects are inhibition of platelets, gastrointestinal injury, hypertension, renal injury and increased risk cardiovascular events.
      1. Do prevent platelet inhibition by aspirin in vitro (therefore consider avoiding e.g. if h/o CAD on ASA): ibuprofen, naproxen, nimesulide, oxaprozin, piroxicam, flufenamic acid, dipyrone and celecoxib
      1. Do not prevent platelet inhibition by aspirin in vitro: diclofenac, ketorolac and ketoprofen. 
      1. Sometimes if one class of NSAID doesn’t work well, switching to another class works better:
         1. Salicylates: Aspirin, Diflunisal, Salsalate
         1. Acetic acid derivatives: Diclofenac, Etodolac, Indomethacin, Ketorolac, Nabumetone, Sulindac, Tolmetin
         1. Enolic acid (Oxicam) derivatives, Meloxicam, Piroxicam
         1. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen, Fenoprofen: Flurbiprofen, Oxaprozin
         1. Anthranilic acid derivatives (Fenamates): Mefenamic acid:

•  
  • Tramadol
    • Weak activity at mu (opioid) receptors and also has some inhibition of serotonin and norepinephrine uptake. Similar side effect profile to mild opioids but has been shown to relieve both neuropathic pain (Duhmke, 2004) as well as fibromyalgia.
    • Potentially habit forming like opioids, therefore use with caution
    • Decrease the seizure threshold especially with neuroleptics and antidepressants. Caution if co-morbid psych.
  • Opioids
    • Background:
      • Endogenous opioid system normal functions include stress-induced analgesia, social affiliation/bonding including maternal-infant bonding, rewards for natural pleasures such as sex and eating. Opioids often used as a substitute for social connection.
        • Emotional pain such as social rejection has similar neurobiology to physical pain on fMRI, etc.
    • Very effective for acute severe pain.
    • Chronic pain is not very satisfactorily managed with opioids because of peripheral and central sensitization. 
    • Problems with opioids: Chronic opioids (especially morphine & fentanyl) lead to tolerance and may lead to opioid induced hyperalgesia (OIH). OIH is apparently uncommon & a dx of exclusion, but some pain specialists believe is very common. Hypothetical mechanisms of OIH: activation of spinal dynorphin, bradykinin receptor, toll-like receptor-4 on glial cells, resulting in a pro-inflammatory state that manifests clinically as increased pain. Opioid-overuse headache is a phenomenon similar to opioid-induced hyperalgesia, which derives from a cumulative interaction between central sensitization, due to repeated activation of nociceptive pathways by recurrent headaches, and pain facilitation due to glial activation. Hypogonadism is especially common in chronic long-acting opioid use. Chronic opioids associated with multiple other adverse effects including increase MI.
    • OIH tx strategies: wean down analgesics. Clonidine, buprenorphine. Early studies that curcumin may benefit (UI: 23273833).
    • Issues with opioids:
      • Research sparse and does not support long-term efficacy, but strongly documents harm.
        • Long-term opioid therapy is associated with lower rates of recovery from chronic pain and return to work.
        • Aversive selection– patients at highest risk of misuse such as h/o psych & substance abuse disorders are most likely to be prescribed high risk long term opiates
        • Lots of diagnoses that don’t necessarily correlate with a patient’s pain. For example, a patient may have documented disc bulges and degenerative disc disease on x-ray/MRI, but the actual main driver of their pain is para-lumbar myofascial dysfunction with poor eating and gut dysbiosis, sedentary habits with deconditioning and disturbed mood and sleep habits and high stress all leading to central sensitization. Doctor’s visits are short and careful psychological and lifestyle evaluation is often minimized. Patients get attached to their diagnoses such as ‘arthritic spine’ and come to believe the locus of control for healing their pain is external-a pill or procedure – and out of their control, leading to low self-efficacy. 
        • Dramatic increase in misuse/abuse/deaths with increased prescription of opiates, which is proportional to mainly length of use but also dose of opiates – odds ratio for misuse/abuse increases >100X in high dose chronic opioid use! Most heroin addicts started their habit with a prescription opioid.
        • Immunosuppression
        • Brain inflammation: glial cells that surround neurons produce inflammatory cytokines, will react to trauma with an inflammatory state in their neocortex which may predispose to psychological disorders such as depression and anxiety. Opioids may aggravate this.
        • Opiate use associated with double fractures incidence in > 60 y/o.
        • Maternal use associated with neonatal abstinence syndrome, low birth weight
        • Monitoring of opioid use:
          • Use ‘Comprehensive urine drug screen’ and follow CDC and state guidelines
  • Anti-epileptics
    • Gabapentin
    • Pregabalin
    • Carbamazepine
  • Neurohormone reuptake inhibitors
    • TCAs
      • Amitriptyline: strong anti-cholinergic effects. Start at 10 mg qHS and slowly titrate as needed
    • SNRIs
      • Duloxetine
      • Venlafaxine
  • Muscle relaxants
    • Cyclobenzaprine
  • Addiction opioids
    • Methadone – can prolong QT – monitor EKG
    • Buprenorphine (requires special certification to prescribe for addiction, but NOT for general treatment)
  • Topicals
    • Lidocaine patch
    • Capsaicin
    • NSAID topicals
  • Compounded mixtures, e.g. gabapentin, ketoprofen, ketamine, amitriptyline
• Summary on Integrative chronic pain treatment:
  • Highly recommend Integrative Medicine pain specialist consultation for all chronic pain patients
  • Pain specialists invaluable for specific pain generator issues, e.g. epidural for discogenic CLBP and to guide/take over if need high dose opioid pain meds
  • Palliative care specialists also invaluable for many non-curable pain situations
  • Minimum 30 minute visit
  • Gather a team
  • Nutrition consult in all chronic pain patients. Assess and correct dysbiosis.
  • Consult movement specialists, especially mind-body integration experts, e.g. Tai Chi, Yoga teachers
  • Mindfulness based programs should be core in chronic pain treatment protocols. Encourage daily meditation in all chronic pain patients.
  • Treat using chronic opioids like using chronic steroids – only with great caution and if clear, robust benefits compared to risks

• Further questions to be explored:Do chronic opioids lead to dysfunction, atrophy of or even damage to the endogenous pain control mechanism, similar to how corticosteroids lead to secondary adrenal insufficiency?How common is opioid induced hyperalgesia, and what are factors increasing the risk?
• Special situations and conditionsComplex Regional Pain Syndrome (CRPS)– potentially devastating and difficult-to-treat chronic neurological pain syndrome that arises from an abnormal response to an often innocuous injury. Prolonged versions of the normal injury response. Most cases however, are not diagnosed for years. Though may resolve, sometimes the pain is so severe that lives are destroyed, and suicides are not uncommon. Primary care physicians often miss it. Type 1 is RSD; Type 2 is causalgia after a nerve injury.Key questions to pick up CRPS:Is the breeze from the heat/ air conditioning/ fan intolerable?Does the weight of a bed sheet bother your foot/ leg/ arm/ hand?Does the arm/ hand/ leg/ foot have severe, constant, burning and/or deep aching pain?Is there a prolonged after-sensation of pain (hyperpathia)?If the answer to any of these is ‘yes,’ and the pain has been there for less than 3 – 6 months, immediately start aggressive treatment: double dose Medrol dose pack, PT including desensitization, and mirror therapy, analgesics. Once the ‘grace period’ is over, CRPS signs and symptoms include:Skin, hair and nail changesVasomotor and sudomotor changesSwellingSensory changesAbnormalities in X-ray (patchy osteoporosis) and triple phase bone scansBiomechanical and movement abnormalitiesSpreading of the pain, either in the same limb, to the opposite limb, or anywhere in the bodyIf not treated in the first 3 months, the changes can rapidly render this a decades-long pain syndrome.  Can try Serotonin norepinephrine reuptake inhibitors (SNRIs), Pregabalin, gabapentin, Tricyclic anti-depressants (TCAs), topical Lidocaine, opioids, tramadol, baclofen, amantadine 100 mg BID, ketamine. Refer to specialist who does interventional procedures such as stellate ganglion blocks may be appropriate. Barriers to the healing of nerves and blood vessels, including tobacco use, excess alcohol, hyperglycemia or diabetes, cardiovascular impediments, malnutrition, and subclinical polyneuropathy, may require treatment.
  • Good resources for patients:
    • Butler, D. and Moseley L., Explain Pain, NIO Group Publications, 2003. An evidence-based book written for the purpose of teaching patients the nature and better management of chronic pain.
    • Melzack, R. and P.D. Wall, The Challenge of Pain, 2nd ed., London: Penguin. 1996. Another fantastic book written for the public on the nature of pain.
    • Nicholas, M., et al., Manage Your Pain. Sydney: ABC Books. 2000. This is a self-help book written by the pain management team at Royal North Shore Hospital in Sydney, Australia.
    • Sopolsky, R. M., Why Zebras Don’t Get Ulcers: An Updated Guide to Stress, Stress Related Diseases, and Coping. A still timely classic. New York: W.H. Freeman and Co. 1998.

• Abbreviations: CLBP = Chronic low back pain, LBP = Low back pain, SS = Sickle cell disease, RA = Rheumatoid arthritis, Tx = treatment