Pain Types and Medical Treatments

Timothy J. Ives, Pharm.D., M.P.H., FCCP, CPP Eshelman School of Pharmacy, and Division of General Medicine and Clinical

Epidemiology, Department of Medicine, School of Medicine The University of North Carolina at Chapel Hill

Timothy_Ives@med.unc.edu

March 14, 2018

Goals for Today 1.  Understand various types of pain.

2.  Describe the basic pharmacotherapy of agents used to manage pain.

3.  Discuss briefly the background to the Opioid Epidemic.

4.  Answer any questions, allay fears, and dispel myths related to pain management.

Epidemiology of Pain What is Pain?

• An unpleasant sensory and emotional experience associated with actual or potential tissue damage. Consisting of Nociception, Pain, Suffering, and Associated Pain Behaviors.

• Pain is whatever the experiencing person says it is

• May not be directly proportional to amount of tissue injury. • Body’s defense mechanisms: warns the CNS that its tissues may

be in jeopardy

• May be triggered without any physical damage to tissues. • Highly subjective, leading to under-treatment

General Types of Pain

!  Acute pain: the primary reason people seek medical attention and the major complaint that they describe on initial evaluation. Results from disease, inflammation or injury to tissues; generally comes on suddenly and may be accompanied by anxiety or emotional distress.

!  Chronic Pain: Widely believed to represent disease itself and can be made much worse by environmental and psychological factors; persists over a long period of time and is resistant to most medical treatments. Emotionally and physically debilitating, a leading cause of suicide.

!  Psychogenic pain: Pain specifically attributable to the thought process, emotional state, or personality of the patient in the absence of an organic or delusional cause or tension mechanism.

A Few Pain Terms • Addiction: Compulsive, chronic drug use despite real and potential

danger to oneself and to others. Cravings, tolerance (gradually requiring a higher dose in order to produce the same effect) and withdrawal are all symptoms.

• Adjuvant analgesic: Medication not primarily indicated to impact pain, but does alleviate some degree of pain, primarily neuropathic pain.

• Arthritis: One or more joints is inflamed, with symptoms of stiffness or even pain.

• Hyperalgesia: Extreme pain experienced as a result of an action or event that does not usually result in pain. Newest cause: Opioids!

• Nociceptor: Sensory receptors that respond to pain-inducing stimuli • Wind-up: Increased sensation of pain from continuous activation of

the pain transmitters in the same area of the body • Withdrawal: Symptoms resulting from rapidly halting the use of a

chronically used medication

More pain language… Narcotic: An obsolete term used to refer to what is now called opioid or opiate. Current usage is primarily in a legal context.

Opiate: Natural substances that come from opium which can be extracted from the opium poppy (e.g., morphine, codeine)

Opioid: Synthetic (e.g., methadone or fentanyl) or semi-synthetic (e.g., oxycodone, hydrocodone) products that work by binding to the same receptors as opiates

Acute Pain

Pain lasting < 3 months (fracture, post-op pain); subsides once the healing process is accomplished.

• Highly correlated to damage • Anxiety abates w/treatment • Sharp, stabbing, agonizing • Localized to specific pain generators • Predictable duration (usually) • Responsive to standard treatment modalities

Chronic Pain Pain lasting > 3 months (neuropathic pain, arthritis); constant and prolonged, sometimes, for life

• Serves no useful function • May be pain that was acute but persists past the healing

phase • No direct relationship to original injury • Often resistant to treatment • Not correlated to tissue damage; often associated w/

psychopathology or coping problems • Typically does not respond to drugs very well; more likely

to abuse alcohol/drugs • Activity is the best medicine

Chronic Pain Non-malignant: • Pain persists beyond the precipitating injury • Rarely accompanied by autonomic symptoms • Sufferers often fail to demonstrate objective evidence of

underlying pathology. • Characterized by location: visceral, myofacial, or

neurologic causes. Malignant: • Has characteristics of chronic pain as well as symptoms of

acute pain (breakthrough pain). • Has a definable cause (e.g., tumor recurrence) • In management, dependence to opioids is generally not a

concern.

Different Types of Pain • Nociceptive pain (abnormal stimuli from somatic and

visceral structures) - sprains, bone fractures, burns, bruises • Deep Somatic: Bone, muscle connective tissue, joints • Shallow Somatic: Skin, tendons, ligaments • Visceral: Organs, cavity linings

• Neuropathic pain (stimuli abnormally processed by the nervous system) - shingles, phantom limb pain, carpal tunnel syndrome, peripheral neuropathy

• Mixed category pain (complex mixture of nociceptive and neuropathic) – migraine headaches

• Psychogenic/Central pain (emotional and/or spiritual stimuli, with dysfunction of nervous system) - fibromyalgia

Neuropathic Pain • Abnormal processing of the impulses either by the peripheral

or central nervous system

• May be caused by injury (amputation and subsequent phantom limb pain), scar tissue from surgery (back surgery high risk), nerve entrapment (carpal tunnel), or damaged nerves (diabetic neuropathy)

• Unclear why depolarization and transmission of pain impulse are spontaneous and repetitive

• Some analgesics relieve pain primarily by decreasing the sodium and potassium transfers at the neuron level, thereby slowing or stopping pain transmission (examples: local anesthetics, or anticonvulsants used for neuropathic pain, migraines.

Common Misconceptions about Pain • Your caregiver or primary care provider is the best judge of pain. • A person with pain will always have obvious signs such as

moaning, abnormal vital signs, or not eating. • Pain is a normal part of aging. • Addiction is common when opioid medications are prescribed.

• Morphine and other strong pain relievers should be reserved for the late stages of dying.

• Morphine and other opioids can easily cause lethal respiratory depression.

• Pain medication should be given only after you develop a worsening of pain.

• Anxiety always makes pain worse.

Substances released when you are in pain

These neurotransmitters, released from traumatized tissue, mediate pain and inflammation:

•  prostaglandins •  bradykinin •  serotonin •  substance P •  histamine

• Non-steroidal anti-inflammatories (NSAIDs), such as ibuprofen, minimize the effects of these substances released, especially prostaglandins.

• Corticosteroids, such as dexamethasone used for cancer pain, also interferes with the production of prostaglandins.

Why Treat Pain? Tissue damage has the potential to elicit mechanisms that can create disabling, refractory, chronic situations that may prolong and even outlast the period of healing.

Analgesia should be viewed not only as a humanitarian gesture, but also a therapeutic maneuver with the goal being the early restoration of function and the mitigation of a chronic debilitated state.

Hedderich R, Ness TJ. Analgesia for trauma and burns. Crit Care Clin. 1999;15(1):167-184.

Brief Pain Inventory: Pain Measurement Scales (or Not)

• Poor appetite and weight loss • Disturbed sleep • Withdrawal from talking or social activities • Sadness, anxiety, or depression • Physical and verbal aggression, wandering, acting-out

behavior, resists care • Difficulty walking or transferring; may become bed bound • Skin ulcers • Urinary incontinence • Increased risk for use of chemical and physical restraints • Decreased ability to perform ADL’s • Impaired immune function

Consequences of Untreated Pain

Common Sense Rules of Pain Management • Set a goal of reduction of pain to tolerable levels, not a goal of

complete relief. Make sure all are aware of the goals

• Use the lowest effective of the simplest single agent, and dose it by the simplest route. Maximize its potential before adding other drugs: “Start low and go slow”

• Be vigilant at assessing the side effects/drug interactions: Treat or prevent side effects, such as constipation and nausea

• Older persons report pain differently and may have fluctuating pain levels and require rapid titration or frequent breakthrough medications

• Frequent clinic visits at first to assure, validate, and titrate • Re-evaluate medications regularly and adjust when necessary

Examples of Chronic Pain Conditions • Arachnoiditis • Avascular Necrosis (AVN) • Brachial plexopathy • Cancer pain • Central Pain Syndrome (CPS) • Crohn’s Disease • Degenerative Disk Disease • Diabetic Neuropathy • Endometriosis • Fibromyalgia • Headache •  Interstitial Cystitis •  Irritable Bowel Syndrome • Low Back Pain • Lyme Disease • Migraine Headache • Multiple Sclerosis • Myofascial Pain Syndrome

• Osteoarthritis • Osteoporosis • Pancreatitis • Pelvic Pain • Peripheral Neuropathy • Phantom Limb Pain • Plantar Fascitis • Psoriatic Arthritis • Raynaud’s disease • Reflex Sympathetic Dystrophy • Rheumatoid arthritis •  Scoliosis •  Shingles •  Systemic Lupus Erythematosis • Temporomandibular Joint (TMJ)

Syndrome • Trigeminal neuralgia • Vulvodynia

Non-opioid (aspirin,

acetaminophen, ibuprofen, etc.)

Opioid (codeine, morphine,

oxycodone, tramadol)

Adjuvants (anticonvulsants, TCAs,

SSRI/SNRI antidepressants)

Drugs Used For Pain Management

Non-Opiate Analgesics These agents act peripherally: • NSAIDs, COX-2 inhibitors

(ibuprofen (Advil), Celebrex, Aleve, etc.): effective in minimizing pain because they minimize the effects of these substances released, especially prostaglandins. Note: 1 in 5 taking NSAIDs exceed the maximum dosage.

• Corticosteroids (prednisone, cortisone, dexamethasone): Also interferes with the production of prostaglandins

Kaufman DW, et al. Exceeding the daily dosing limit of nonsteroidal anti-inflammatory drugs among ibuprofen users. Pharmacoepidemiol Drug Saf. 2018; 27:322-331.

Adjunctive and Other Medications Some analgesics relieve pain primarily by decreasing the sodium and potassium transfers at the neuron level, thereby slowing or stopping pain transmission. Examples: local anesthetics, anticonvulsants used for neuropathic pain, migraines. • Antidepressants (amitriptyline, duloxetine, venlafaxine) • Anticonvulsants (gabapentin, topiramate, carbamazepine, zonisamide) • Antihistamines (hydroxyzine, diphenhydramine) • Antipsychotics (chlorpromazine, promethazine, haloperidol) • Benzodiazepines (diazepam, clonazepam, lorazepam) • Cannabinoids (dronabinol, marijuana) • Local Analgesics (lidocaine, capsaicin) • Placebos (30 to 40% positive response) • Stimulants (amphetamine, caffeine, cocaine) – potentiate opiate’s action

Evanoff AB, et al. Physicians-in-training are not prepared to prescribe medical marijuana. Drug Alcohol Depend. 2017; 180: 151-155.

Are There Any New Opioid Medications? More Importantly, Do Opiates Really Work?

From an advertisement of 1863. W.I.P.A. = Opium in an ethanol vehicle = Tincture of Opium = Laudanum

Opioids • Chemicals that work by binding to opioid receptors, which are

found principally in the CNS and the GI tract. • Analgesic effects of opioids are due to decreased perception of

pain, decreased reaction to pain, as well as increased pain tolerance.

• Side effects include sedation, respiratory depression, and constipation.

• Physical dependence can develop with ongoing administration of opioids, leading to a withdrawal syndrome with abrupt discontinuation.

• Produce a feeling of euphoria, and this effect, coupled with physical dependence, can lead to recreational use of opioids by many individuals.

Receptor Binding at Mu Receptor

Agonist: Morphine-like effect (e.g., heroin, weak binding except for fentanyl) Partial Agonist: Weak morphine-like effects with strong receptor affinity (e.g., buprenorphine)

Antagonist: No effect in absence of an opiate or opiate dependence (e.g., naloxone, naltrexone). Opioid antagonists are opioid-like substances that bind to opioid receptors but produce little or no agonist activity. They are used mainly to reverse symptoms of opioid overdose, particularly respiratory depression.

Opiate Receptors and Effects Exerted

Mu1 (μ1) analgesia, euphoria, euphoria, addiction

Mu2 (μ2) constipation, respiratory depression

Kappa Analgesia (spinal), sedation, dysphoria

Delta analgesia, anti-depressive, dependence

Schematic of Mu Opiate Receptor:

Morphine Mg Equivalents (MME) Opioid (dose, in mg/day) Codeine 0.15

Fentanyl transdermal (in mcg/hr) 0.5 Hydrocodone 1

Hydromorphone 4 Methadone:

1-20 mg/day 4

21-40 mg/day 8 41-60 mg/day 10

≥ 61-80 mg/day 12 Morphine 1

Oxycodone 1.5

Oxymorphone 3 Tramadol 10

Tapentadol 2.5 Atlanta, GA: Centers for Disease Control and Prevention; 2016. Technical Assistance Guide No. 01-13: Calculating Daily Morphine Milligram Equivalents. www.pdmpassist.org/pdf/BJA_performance_measure_aid_MME_conversion.pdf.

Opioid Side Effects • Constipation: need proactive laxative use

• Nausea/vomiting: consider treating with dopamine antagonists and/or prokinetics (metoclopramide, domperidone, prochlorperazine, haloperidol)

• Urinary retention: anticholinergic

• Itch/rash (pruritus): worse in children. Can try antihistamines, however not a great success

• Dry mouth

• Respiratory depression: uncommon when titrated in response to symptoms; more common with overdose

• Mental clouding, excess sedation

• Neurotoxicity: delirium, myoclonus seizures

OXY

Know any of these? Red Flag Behaviors

• Makes frequent ED visits, urgent care visits, or walk-ins • Can’t tell you where the pain is, but tells you about all of the

MVAs or surgeries that they’ve had

• Visits multiple provider’s offices (doctor shoppers/collectors) • Has an unusually high knowledge of controlled substances • Refuses all alternatives to controlled substances

• Last patient in the door (Friday at 4:45 PM Syndrome), or • 8:45 PM Syndrome in Pharmacies = Often fills prescriptions

after normal office hours when the pharmacist cannot call PCP to confirm (e.g., Friday nights).

More Red Flag Behaviors! • Claims to be unable to reach or get an appointment with their regular provider.

• Brings old records, x-rays or MRIs to the office visit.

• Has multiple drug allergies, except one (guess which one?) • Claims to have lost, run out of, or had their prescription stolen (and has “filed a police report”).

• Usually pays cash, but also has insurance or Medicaid • Will use elderly parents, relatives, or children to obtain prescriptions

• Newest: Bringing abused animals to the vet to get drugs

National Survey on Drug Use and Health, Substance Abuse and Mental Health Services Administration, 2012

Source of the Drug Involved in the Overdose Death

New Term: Opioid Activation Syndrome

Related to dependence formation, impulsivity, irritable mania, opioid-induced hyperalgesia

Lee M, et al. A comprehensive review of opioid-induced hyperalgesia. Pain Physician. 2011; 14(2):145-61.

Five Causes of the Current Opioid Epidemic 1.  Pain as the “Fifth Vital Sign”: A subjective measurement, from the

American Pain Society/Joint Commission, with no improvement in pain control since the 1990 introduction. It still persists, with little evidence.

2.  Unrealistic patient expectations regarding chronic pain management: Can opioids/anything completely ablate pain? See #1.

3.  Very bad statistics: 1980 Letter to the Editor in NEJM: 0.03% dependency rate?

4.  The marketing of OxyContin and Duragesic in the 1990’s: With false assurances of both safety and efficacy, based upon #3, and others.

5.  Neuroexcitatory effects of oxycodone, oxymorphone, and hydromorphone: No one ever asks for morphine anymore. Also, why do they call it “Percocet”?

Mularski RA, et al. Measuring pain as the 5th vital sign does not improve quality of pain management. J Gen Intern Med. 2006; 21: 607–612. Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980; 302:123.

North Carolina: Naloxone Standing Orders •  In the Past: More than 1,000 people died each year in North

Carolina from prescription opioid and heroin overdoses.

•  As of 6.20.16, North Carolina pharmacies can make naloxone available without a prescription, the third state to issue a statewide standing prescription order.

•  Good News: In 2015, the number of opioid overdose reversals exceeded the number of overdose deaths.

•  As of 3.1.18 (and since 8.1.13), # overdose reversals via naloxone in North Carolina = 10,369

Which North Carolina Pharmacies Have Naloxone?

Via standing order, pharmacies (> 1,300 pharmacies in North Carolina) can dispense naloxone to: •  Persons who are at risk of experiencing an opiate-related overdose. •  Persons who are the family member or friend of a person at risk of experiencing

an opiate-related overdose. •  Persons who are in the position to assist a person at risk of experiencing an

opiate-related overdose. http://www.naloxonesaves.org/n-c-pharmacies-that-offer-naloxone/

If You Are Taking an Opioid Chronically, Do You Have an Opioid Care Plan?

A written “Plan of Care for Pain Management with Opioids” should include …

• Your actual diagnosis/diagnoses • Goals of management (e.g.,. maximize quality of life & the level of daily function)

• Ways to help you reach those goals • Your specific plan of care • Follow-up instructions for care

Don’t Forget Non-Drug Interventions • Weight Loss programs • Massage • Acupuncture • Diversion (leisure and recreation) • Relaxation therapy (aka stress reduction) • Yoga, tai chi • Hypnosis • Cognitive-behavioral interventions (to reduce pain and pain-related

disability and help patients cope by selectively reinforce new and more adaptive coping behaviors.

•  incremental gains in function •  changes in relationships at home •  use of relaxation techniques, mindfulness, hypnosis, or biofeedback •  graduated levels of exercise •  decreases or eliminates maladaptive pain behaviors

A Few of My Pain Management Pearls 1.  Nothing lasts forever: Accept “Rotating the Crops” 2.  Always anticipate and treat constipation 3.  Pain scores are never as important as your overall function 4.  Mood directly influences pain perception (and vice versa) 5.  Think about combination therapy for most chronic (and

sometimes, acute) pain syndromes (1 + 1 = 3) 6.  Topical pain therapy is less toxic than oral medications 7.  Opioids big problem: They don’t last, acutely or

chronically. Newest evidence: Consider deprescribing. 8.  Drugs are usually fourth-line therapy for chronic pain

(what are the first 3?)

What are Your Responsibilities as a Patient with Pain?

1.  Always report pain as it is NOT a normal part of life 2.  Use relaxation methods to decrease muscle tension.

Also, consider tactile strategies like massage, tai chi, music, art, and meditation which can be very helpful

3.  Talk to your primary care provider about all options before considering invasive procedures (e.g., surgery)

4.  If not satisfied, get second opinion 5.  Take analgesics when you need them, don’t save

them for later 6.  Avoid peaks and valleys, in life, in pain

Drug Disposal in Household Trash • Always ask about Take-Back programs where you are seen/

your pharmacy

• Only if no medication take-back program, then dispose of most medications in the household trash: • Mix (do NOT crush tablets or capsules) with a substance such as kitty

litter or used coffee grounds; • Place the mixture in a container such as a sealed plastic bag; • Throw the container in your household trash.

• Before disposing empty prescription vial, scratch out all information on the prescription label to make it unreadable.

• If using a transdermal fentanyl patch, do not flush used or unneeded patches down the sink or toilet (gets into the water source used by all)

Summary • Pain is a subjective experience, and is influenced by many

factors, and not just physical processes

•  Some chronic changes in the nervous system may not be reversible

• Start pharmacotherapy in stepwise manner, matching the initial analgesic to the level and type of pain

• Medications and therapies are targeted at specific mechanisms

• All interventions, drug and non-drug, should be considered

Any Questions?