Pain and its treatment in psychiatric practice (2) (1)

A D O N I S S F E RA , M D

CHRONIC PAIN IN PSYCHIATRIC PRACTICE

DEFINITION OF ACUTE AND CHRONIC PAIN, NOCICEPTIVE AND NEUROPATHIC PAIN, PERIPHERAL AND CENTRAL SENSITIZATION, PAIN AND MOOD, PHARMACOLOGY OF PAIN, CHRONIC PAIN SYNDROMES

RIVER OF PAIN

Acheron was known as the river of pain, and was one of the five rivers of the Greek underworld.

THE HISTORY OF MEDICINE IS THE HISTORY OF PAIN

• Asclepius, the god of medicine attending to a patient in pain

MORPHEUS AND HIS ELIXIR

TWO PARALLEL HISTORIES: ACUTE AND CHRONIC PAIN

Acute Pain Chronic Pain

Physiological: protective (survival benefit)

Pathological: non-protective (no survival benefit)

Causes external: obvious Causes internal: obscure

Tissue damage: resolution within days/weeks

CNS changes: may not resolve

Attended by physicians (illness) Attended by clergy (suffering)

Symptom of illness Existential: a social phenomenon

The demon is outside The demon is within

CHRONIC PAIN: A WAY OF LIFE

• Headaches, backaches, pain in amputated limbs, causalgias and neuralgias have always existed, but the sufferers were not always considered “ill”.

“A WAY OF LIFE” IN OUR SOCIETY

• Destitution, Poverty, Homelessness affect health, yet are not being addressed by medical science (a way of life).

MEDICALIZATION OF CHRONIC PAIN

• In March of 1899 Felix Hoffman discovered Aspirin.

• Aspirin was more than a drug – it changed the way of thinking about chronic pain.

• Pain and suffering became medicalized (medical model applied).

A CULTURE OF PAIN AND PAINKILLERS

• In 2005 more than 10 million Americans were abusing prescription medications – which is more than the combined number of people abusing cocaine, heroin, hallucinogens and inhalants.

• Prescription painkiller overdoses killed nearly 15,000 people in the US in 2008 (three times the 4,000 people killed by these drugs in1999).

Scott M. Fishman, MD; Responsible opioid prescribing a physician’s guide; Waterford Life Sciences, 2007

A “PERFECT STORM” OF CONTROVERSY

*War on pain *War on drugs

• Physicians are being enlisted on both fronts:

-combating pain

-reducing the risk of diversion, abuse and addiction.

PHARMACOVIGILENCE

• The science of detecting, understanding and preventing adverse effects or any other drug related problem.

PAIN: DEFINITION

• “An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage” (International Association for the Study of Pain (IASP).

PAIN - A LEARNED EXPERIENCE

• Each individual “learns” pain through experiences related to injury in early life.

To hear about pain is to have doubt; to experiencepain is to have certainty. (Elaine Scarry: The Body in Pain)

PAIN THAT IS PRONE TO BECOME CHRONIC

• Type: post-op, post trauma, post-herpes

• Neuropathic component: nerve injury

• Disability and compensation

• Inadequate analgesia

• Prolonged pain before surgery

• Repeated surgeries

• Radiation or chemotherapy

• Psychiatric vulnerabilities

CLASSIFICATION OF CHRONIC PAIN

Inflammation or mechanical damage

Classic examples-osteoarthritis-rheumatoid arthritis

Damage or entrapment of peripheral nerves

Classic examples-diabetic peripheral neuropathic pain-post-herpetic neuralgia

Central disturbance in pain processing

Classic examples-fibromyalgia-IBS-headaches-LBP-TMJ disorder-Chronic pelvic pain

Perpheral (nociceptive)

Neuropathic Central (non-nociceptive)

ALLODYNIA AND HYPERALGESIA

Allodinia = Pain evoked by innocuous stimuli.

Hyperalgesia = exaggerated pain produced by mildly painful stimuli.

NOCICEPTION (THE AFFERENTS)

-A beta fibers respond only to non-noxious stimuli-A delta and C fibers respond to noxious mechanical, heat, and chemical stimuli.

Stephen M. Stahl;Stahl’s Essential Psychopharmacology; Third Edition;Cambridge University Press 2008

NOCICEPTION AND NEUROPATHY

1. Sensory Pathway =information about the location and intensity of the painful stimulus (spinothalamic tract).

2. Emotional Pathway =affective component of the pain experience (spinobulbar tract).

Combined data from these pathways = human subjective experience of pain.

INSULAR CORTEX – WHERE PAIN BECOMES SUFFERING

VON ECONOMO NEURONS (VEN): INSULA AND ACC

THE PHYSIOLOGY OF INSULAR CORTEX

The insulae are believed to be involved in:• emotion • pain• empathy• perception, • self-awareness, • cognitive functioning, • interpersonal experience.

EMPATHY IS PAIN … SORT OF

VEN in Insula and Anterior Cingulate Cortex (ACC) are activated when subjects evaluate painful stimuli and when empathizing with others who experience physical pain.

The Neural Basis of Empathy;Annual Review of Neuroscience,Vol. 35: 1-23 (Volume publication date July 2012);DOI: 10.1146/annurev-neuro-062111-150536

VON ECONOMO NEURON DISCOVERED IN THE INSULA OF MACAQUE MONKEYS

• Published on June 4, 2012: A scientist from the Max Planck Institute discovered that von Economo neuron (VEN) is also found in the insula of macaque monkeys

PERIPHERAL SENSITIZATION (PRIMARY HYPERALGESIA)

SENSITIZING SOUP

• Hydrogen ions• Noradrenaline• Bradykinin• Histamine• Potassium ions• Prostaglandins• Purines• Cytokines• Serotonin• Nerve growth factor• neuropeptides

PERIPHERAL SENSITIZATION LEADS TO CENTRAL SENSITIZATION

CENTRAL SENSITIZATION (SECONDARY HYPERALGESIA)

PAIN BEGETS MORE PAIN (OVERACTIVE ASCENDING PATHWAYS)

Long term potentiation (LTP) is perpetuated by pain and leads to strengthened synapses.

These stronger synapses are able to:recruit subliminal inputs.

CAUSES OF SENSITIZATION?

When a nerve is severed, the distal portion degenerates and dies.

The proximal portion sprouts trying to reach the previous target tissue.

The sprouts lack guidance and form tangeled neuromas.

Neuromas generate ectopic activity and heightened sensitivity to mechanical, thermal and chemical stimuli.


EPHAPTIC CROSS-TALK

Disruption to myelination may also allow cross-talk between neurons(ephaptic cross- talk).

The electrical activity in an A beta fiber neuroma can electrically stimulate activity in a C fiber.

Repetitive firing of one neuron can stimulate activity in the neighboring neurons(hyperalgesia and allodynia).


FUNCTIONAL SOMATIC SYNDROMES (FSS)

• Fibromyalgia• Irritable bowel syndrome• Chronic Fatigue Syndrom• Temporomandibular Joint Disorder• Interstitial cystitis

Patients with one FSS often suffer from one or moreother FSS as well as psychiatric comorbidity.

THE COMPLEX RELATIONSHIP BETWEEN PAIN AND DEPRESSION

• The overlap between pain and depression ranges from 30% - 60%

• Depression may lower pain threshold (depressed people fell more pain)

• Pain may precipitate depression

• Patients with chronic pain are at higher risk of developing depression

• Pain and depression may be considered integrated.

Gallagher RM, Verma S. Semin; Clin Neuropsychiatry 1999; 4 :203-220;Von Korff M, Simon G; Br J Psychiatry.1996;168 (sup 30):101-103

PAIN PATIENTS IN PSYCHIATRIC PRACTICE

Psychiatrist: Somatization d/o

Rheumatologist: fibromyalgia

Neurologist: chronic fatigue syndrome/myalgic encephalomyelitis

Patient: “multiple chemicalsensitivities”

WAR ON PAIN (FRONTS)

SNRI DRUGS APPROVED FOR CHRONIC PAIN

Duloxetine Milnacipran

60 mg once daily; higher doses increase SEs without increasing efficacy in pain disorders

30-200 mg/day in 2 doses

Approved for multiple neuropathic pain disorders

Approved for fibromyalgia

SEs include nausea, dry mouth; can cause urinary retention, rare activation of suicidality, rare hepatotoxicity

SEs: nausea, constipation, sweating, urologic complaints, urinary hesitancy, dose-dependent increase in blood pressure; can cause rare activation of suicidality

Metabolized by CYP 450 2D6 Few known adverse pharmacokinetic drug interactions

Not for use with Thioridazine, MAOIs, or patients with uncontrolled narrow angle glaucoma or hepatic impairment

Not for use with MAOIs, or patients with uncontrolled narrow angle glaucoma or hepatic impairment

OTHER SNRI DRUGS

Venlafaxine Desvenlafaxine

75-225 mg once daily 50 mg once daily

Clinical efficacy in reducing chronic pain Clinical efficacy in reducing chronic pain

SEs include headaches, insomnia, nausea, sweating, dose dependent increase in BP, rare activation of suicidality

SEs include insomnia, nausea, constipation, sweating, increase in BP, rare activation of suicidality.

Use with caution in patients with cardiac impairment

Use with caution in patients with cardiac impairment

Not for use with MAOIs or in patients with uncontrolled narrow-angle glaucoma

Not for use with MAOIs or in patients with uncontrolled narrow-angle glaucoma

ALPHA 2 DELTA LIGANDS

Pregabalin Gabapentin

150-600 mg/day in 2-3 doses 900-1800 mg/day in 3 doses

Approved in multiple neuropathic pain disorders

Approved in postherpetic neuralgia

Most common SEs: sedation, dizziness

Most common SEs: sedation, dizziness, fatigue, ataxia, nystagmus, tremor

Enhances slow-wave sleep Enhances slow-wave sleep

Renally excreted Renally excreted

ANTICONVULSANTS FOR CHRONIC PAIN

Carbamazepine

Oxcarbazepine

Topiramate Lamotrigine Zonisamide

1200 mg/day; start slow

1200-1400 mg/day; start slow

50-300 mg\day 100-300 mg/day

100-600 mg/day

Approved for trigeminal neuralgia; may have efficacy in other neuropathic pain disorders

Adjunct for neuropathic pain

FDA approved for migraine prophylaxis

Clinical efficacy in neuropathic pain

Some clinical efficacy in neuropathic pain and migraines

Induces P450 enzymes, may lower the levels of other drugs

Less Induction of P450 enzymes

May have efficacy in other neuropathic pain disorders.

Efficacy can wane after several weeks of use

TRICYCLICS FOR CHRONIC PAIN

Amytriptiline Cyclobenzaprine

25-50 mg once daily 15 mg/day in 3 doses

Used for multiple pain disorders 15-30 mg/day in one dose (ER)

SEs include sedation, weight gain, anticholinergic effects, dizziness, hypotension

Muscle relaxant

Metabolized to nortriptyline by CYP 450 1A2

Not recommended for long term use

Significant drug-drug interactions SEs: sedation, dry mouth, fatigue headache

Use with caution in patients with renal or hepatic impairment

Use with caution in patients with urinary retention, angle-closure glaucoma, hepatic impairment

Can have cardiovascular effects Can have cardiovascular effects

Multiple contraindications Do not use with MAOIs

ON THE OPIOID BORDER: PROPOXYPHENE AND TRAMADOL

OTHER PAIN AGENTS

NSAIDs Acetaminophen Baclophen

Better for acute pain or for chronic inflammatory pain

Less effect on bleeding and renal function compared to NSAIDs

Muscle relaxant and antispastic

Warning for GI bleeding with SSRIs

Can cause hepatotoxicity at high doses

Used for trigeminal neuralgia and some other neuropathic pain conditions

Combination with lithium may cause lithium toxicity

Many psychotropics are metabolized by the same liver enzymes

Use with caution in patients with renal impairment

OPIOIDS

• Effective for osteoarthritis, rheumatoid arthritis, musculoskeletal pain, postherpetic neuralgia, phantom limb pain, diabetic neuropathy, and chronic low back pain.

• No studies of effectiveness beyond 8 weeks

• Not effective for fibromyalgia

• Risks (dependence, tolerance, pain worsening, reduced effects of SSRIs)

Ballantyne JC, Shin NS; Clin J Pain 2008;24:469-78; Clauw. Am J Med 2009;(Suppl 12):S 3-13

OPIOIDS FOR CHRONIC PAIN: THE TWO FACES OF JANUS

• Opioids may elicit paradoxical “pain” in both animals and humans.

• In humans hyperalgesia is noted in areas of the body different from the site of the original pain complaint.

• Methadone maintenance patients are hyperalgesic.

• The mechanisms of opioid induced hyperalgesia are unknown

Frank Porreca, PHD, University of Arizona, Tucson, Arizona

NONPHARMACOLOGICAL TREATMENTS FOR CHRONIC PAIN

• Cognitive behavioral therapy -May work best if targeted to a specific outcome -Adherence may be an issue

• Hypnosis, relaxation, guided imagery -May reduce pain, distress

• Education -Should be combined with other treatment approaches -Education groups can be useful, but adherence may be low

• Aerobic exercise

EVIDENCE BASED TREATMENT OF CHRONIC PAIN SYNDROMES WITH HIGH PSYCHIATRIC

CO-MORBIDITY

1. Neuropathic Pain 2. Fibromyalgia 3. Chronic Back Pain 4. Osteoarthritis

NEUROPATHIC PAIN

• Diabetic neuropathy - 16% of persons with diabetes.

• Postherpetic neuralgia - up to 25% develop neuropathic pain following an episode of shingles.

• Spinal stenosis – 3% develop neuropathic pain

• Lumbar disc herniation - 4% develop neuropathic low back pain

FIRST LINE DRUGS FOR NEUROPATHIC PAIN

• Gabapentin 900-3600 mg/day (Post-herpetic neuralgia)

• Pregabalin 75-600 mg/day (Diabetic Neuropathy, Post-herpetic neuralgia)

• Duloxetine 60 mg daily (Diabetic neuropathy)

• Topical Agents: Lidoderm up to 3 patches/day (Post-herpetic neuralgia)

Schatzberg A, Nemeroff C; Textbook of Psychopharmacology; The American Psychiatric Publishing, 2009

DIAGNOSTIC CRITERIA FOR FIBROMYALGIA

American College of Rheumatology:1. Generalized pain that is both widespread (on

both the right and the left side of the body, upper and lower halves, and axial as well as proximal arms and legs) and chronic (lasting more than 3 months).

2. Multiple tender points on physical examination (located in the front and back of the neck, upper chest and back areas, iliosacral and posterior gluteal areas, elbows and knees).


FIBROMYALGIA AND ACCELERATED BRAIN GRAY MATTER LOSS

Less gray matter density in fibromyalgia patients vs. controls :

-left parahippocampal gyrus (PHG),-left and right mid/posterior cingulate gyrus (CG)-left insular cortex (IC), and -medial frontal cortex

Anil Kuchinand, P.Schweinhardt, DA Seminowitz et al.; Accelerated brain Gray Mattewr Tissue Loss in Fibromyalgia Patients: Premature Aging of the Brain, Society of Neuroscience 2007

FIBROMYALGIA - PHARMACOLOGIC AND NON-PHARMACOLOGIC TREATMENTS

First line:• SNRIs (Duloxetine, Milnacipran)• Alpha2 Delta ligands (Pregabalin, Gabapentin)• Aerobic Exercise• CBT• Education

Second line:• TCAs• Cyclobenzaprine (chemical structure related to TCAs)• Tramadol


LOW BACK PAIN

• The most commonly prescribed medications for low back pain are:

• NSAIDs, • Muscle relaxants, • Opioid analgesics. • Benzodiazepines, systemic corticosteroids,

antidepressants and anticonvulsants are also prescribed.

• Schatzberg A, Nemeroff C; Textbook of Psychopharmacology; The American Psychiatric Publishing, 2009

LOW BACK PAIN GENE?

A UK study, published in the Annals of Rheumatic Diseases (Sep. 24, 2012):PARK2 gene was linked to age-related degeneration of the intervertebral discs in the spine, a common cause of lower back pain.

LIFT WITH YOUR KNEES NOT YOUR BACK

OSTEOARTHRITIS

• Osteophyte formation

• Focus of treatment: reduction of pain, preservation of function.

• Acetaminophen• NSAID• Aerobic exercise• Opioids

• Not enough evidence for chondroitin, glucosamine and intra-articular hyaluronic acid.

• Antidepressants not studied for pain in osteoarthritis, but Katon 2007 looked at the co-morbidity of osteoarthritis with depression (antidepressants helpful) .


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Pain and its treatment in psychiatric practice (2) (1)