Pain Management

These lectures by Dr. Darin Ramsey occurred on Tuesday, September 21st and Tuesday, September 28th.

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Study Materials
Required reading:
 * Equianalgesic Dosing of Opioids for Pain Management. Pharmacist’s Letter/Prescriber’s Letter 2010;26(7):260712.


 * Opioid Dosing: Focus on Safety. Pharmacist’s Letter/Prescriber’s Letter 2010;26(5):260712.

Handouts: Panopto:
 * Swegle JM, Logemann C. Management of Common Opioid-Induced Adverse Effects. Am Fam Physician. 2006;74:1347-54.
 * Dworkin RH, O’Conner AB, Backonja M, et al. Pharmacologic Management of Neuropathic Pain: Evidence-based Recommendations. Pain. 2007;132:237-251.
 * O’Connor AB, Dworkin RH., Treatment of Neuropathic Pain: An Overview of Recent Guidelines. The American Journal of Medicine. 2009;122:S22-S32.
 * Pain Management
 * September 21st Panopto
 * September 28th Panopto

Appreciate provider, patient, and system barriers to effective pain management.
Pain management is not an easy task. Common causes of treatment failure to be aware of include:
 * Inappropriate or unknown diagnosis/ Stop pretending
 * Misunderstanding of phramacology or pharmacokinetics
 * Inadequate management of adverse effects
 * Fear of addiction
 * Unrealistic goals for therapy
 * Irrational polypharmacy
 * Patient barriers
 * Lack of understanding from any of the parties involved

Define tolerance, Physical dependence, addiction, and psuedoaddiction as they pertain to pain management.
Tolerance - is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug's effects over time. Physical addiction - the body has adjusted to the presence of the drug such that specific withdrawal symptoms will occur if the drug is abruptly removed. Addiction - a primary, chronic neurobiologic disease with genetic, psychosocial, and environmental factors influencing its development and manifestation Pseudoaddiction - often reflective of the fact that patient simply isn't recieving adequate pain control. When pain is finally managed properly, their "drug seeking" behavior disappears
 * With continued dosing, a patient may require more of the drug in order to produce the same percieved benefit
 * Fortunately, adverse effect may also diminish in this way
 * Note: just because a patient has physical dependence does NOT mean they necessarily have an addiction problem
 * Associated with imapired control over drug use, compulsive use, cravings, and continued use despite harm.
 * Identified by a pattern of behaviors that usually become obvious over timeIntervention_allison_Walking_on_sunshine

Acute Pain
Commonly occurs after surgery, trauma, and medical procedures. Known to cause: Typically resolves in 30 days as the incute insult heals
 * Tachycardia
 * tachypnea
 * hypertension
 * diaphoresis
 * mydriasis
 * increased anxiety
 * Postsurgical pain
 * pain due to medical procedures
 * post-trauma pain
 * muscle strains - the brain sends out signals to cause spasms and stabilize the muscles from moving while the injury heals

Chronic Nonmalignant Pain
Pain not associated with a malignant disease and lasting >6 months beyond the healing period. Examples include:
 * Diffuse joint pain
 * Headache
 * Chronic low back pain
 * Osteoarthritis & Rheumatoid Arthritis
 * Fibromyalgia
 * Neuropathic Pain

Chronic Malignant Pain
Pain that is associated with progressive diseas that is potentially life limiting, such as cancer or chemotherapy. It can also have elements of acute pain when tissue damage continues from tumor infiltration. Examples include:
 * Cancer/Chemotherapy
 * AIDS
 * End-stage organ system failure
 * Multiple Sclerosis

Describe the different type of pain intensity scales used to rate a patient's pain
Each scale has its advantages and disadvantages. It doesn't matter which you really use, just make sure you use the same one each time. Anyone can perform a pain screenin, even a pharmacist. The Wong-Baker scale is most commonly used for children 







Describe the components of the Word Health Organization (WHO) three-stage analgesic ladder and apply this approach to recommend appropriate pharmacotherapy to a specific patient


The ladder - describes a stepwise approach for managing pain. It was originally designed for caner pain relief but many clinicians also utilize the approach when treating chronic, non cancer related pain. It essentially a liner decision tree.
 * 1) A patient with pain should start with on level one with a non opioid, and possibly also an adjuvant to pain relief
 * 2) If the patient is still experiencing pain, they can move to level 2 and use an opioid for mild pain, plus a non opioid, and possibly also an adjuvant.
 * 3) if the patient is still experiencing pain, they can move to level 3 and use an opioid for moderate to severe pain, plus a non opioid, plus an adjuvant to therapy. The opioid dose is adjusted accordingly to treat the pain.

NSAID Adverse Effects
There are subtle physiochemical and pharmacokinetic differences between the drugs which affect the side effect profile, but there is limited evidence that these have clinical significance or make any one drug unique.

CNS effects such as drowsiness and confusion are common

Excacerbations of asthma and skin rashes can occur. This is NOT an allergic reaction, but rather a pharmacologic effect associated with prostaglandin inhibition and unopposed leukotriene activity in teh respiratory tract.

NSAIDS can induce renal dysfucntion by Risk factors fo NSAID induced acute nephrotoxicity include Acute renal failure can usually be rapidly reverse by discontinuing NSAID
 * prostaglandin inhibition
 * interstitial nephritis
 * impaired renin secretion
 * enhanced tubular water/sodium reabsorption
 * Congestive heart failure
 * Chronic Renal Insufficiency
 * Cirrhosis with ascites
 * Intravascular volume depletion
 * Diuretic therapy

NSAIDS can cause fluid retention

NSAIDS can also cause an increase in blood pressure through the inhibition of prostaglandins. This causes constriction of arteriolar smooth muscle and changes in extraceulluar fluid volume

The most common and concering adverse effect of NSAIDS are the gastrointestinal effects caused by inhition of the protective effects of prostaglandins on the gastric mucosa. Data supports the risk of peptic uclers with chronic NSAID use, particularly in the elderly. Serious ulceration and bleeding can occur at any time without warning signs. Risk factors include: The risk of gsatric ulceration can be minimzed with the addition of Relative contraindications to NSAID use include: The 2009 American Geriatrics Society Pain Management Guidelines recommend that
 * Over 65 years of age
 * history of peptic ulcer complications
 * High dose or multiple NSAID use
 * Duration of therapy greater than 3 months.
 * H2 receptor antagonist
 * Proton Pump Inhibitor
 * Misoprostol (cytotec) / Misoprostol & Dilcofenac (Arthrotec)
 * Anticoagulation
 * Coagulopathy
 * Thrombocytopenia - too few platelets
 * NSAIDS not be used in frail elderly adults with persistent pain
 * "Elderly" defined here as age greater than or equal to 75.
 * Instead the recommended opioids as the 1st line for pain management therapy, which is controversial because it introduces a host of symptoms including sedation, constipation, and tolerance.

Opioid Adverse Effects
It is important to remember that the success or failure of pain management can depend greatly on the incidence and severity of adverse effects of opioids

Constipation is the most common adverse effect of chronic opioid therapy Nausea and vomiting Drowsiness and Sedation Respiratory Depression Itching or Pruritis Pseudoallergy versus a true allergic reaction. Allergic Drug Class Considerations
 * opioids act at receptors in the GI tract and cause a delay in gastric empyting, a decrease in peristalsis, and a slow down in bowel movement
 * Assess age, fluid intake, and activity level to guage risk for constipation
 * A stimulant laxative is recommended as a component of the bowel regimen
 * Frequently, a stool-softening agent is added: docusate sodium (colace)
 * Patients should be cautioned about using bulk-forming laxatives in the management of opioid-induced constipation
 * Stimulation of the chemoreceptor trigger zone (CTZ)
 * Gastric stasis
 * Enhanced vestibular sensitivity
 * Nausea & Vomiting usually occur at the start of opioid therapy, or with increase in dose
 * Medications used include to treat nausea include:metoclopramide, prochlorperazine, promethazine, chlorpromazine, meclizine, scopalamine, ondasetron, granisetron.
 * Symptoms usually resolve after a few days
 * Symptoms may return if doses are increased significantly
 * Monitor for signs or symptoms of cognitive impairment or hallucinations
 * Occurs if the respiratory rate falls below eight breaths per minute
 * Tolerance usually develops within days to weeks of continued opioid use
 * Typically occurs with a substantial dose increase or if patient has swithced to another opioid incorrectly
 * Treatment: Naloxone (Narcan) should only be used if absolutely necessary. It will reverse the analgesic effects of opioids as well as the adverse effects
 * Potentially caused by the release of histamine
 * Diphenhydramine is often the first antihistamine used, although it may contribue to drowsiness or sedation
 * Symptoms of pseudoallergy include: itching, flushing, and sweating
 * Hives, increased heart rate, and low blood pressure can be due to either pseudoallergy or true allergy.
 * True allergy reactions include:
 * Maculopapular rash
 * pustular rash, bronchospasm,
 * angioedema
 * Allergic cross-reactivity is more likely to occur within each class and less likely with a drug from another analogue class.
 * Naturally occuring and semisynthetic compounds are the most potent histamine releasers
 * The presence of a 6-hydroxyl group may cause erythema and fever

Explain the advantages of ATC dosing versus PRN dosing of analgesic agents
ATC - or "around the clock" means that you're taking something scheduled, it can involve a long acting as well as an immediate release formulation. PRN - means that the drug should be taken as needed, but usually with a limit as to how often the patient can take it.
 * most patients will benefit from a long acting formulation, which eliminates the need for the patient to take the drug every four hours throughout the day
 * this also ensures analgesia throughout the night, allowing for undisturbed sleep
 * It provides a consistent level of pain relief and avoids the peaks and troughs seen with dosing of short acting formulations

Recognize situations in which certain analgesics would be inappropriate
The above section describing adverse reactions to NSAIDS and Opioids, as well as a good dose of common sense, can help identify situations in which certain analgesics are inappropriate.

For example, NSAIDS should probably not be used in patients with Opioids should probably not be used in patients with
 * Acute kidney failure
 * Gastric Ulcers
 * Thrombocytopenia
 * Problems with coagulation
 * advanced age and frailty
 * Congestive Heart Failure
 * Susceptibility to falls/accidents
 * liver dysfunction
 * potential for abuse
 * broad opioid allergy

Using an opioid conversion chart, be able to convert a patient from one pioid agent to an equainalgesic dose of another opioid. (i.e. convert from PO to PO, IV to PO, etc.)
Table A is a standard conversion of equianalgesic opioids. Many practice sites or text books may vary slightly. Its a convenient reference to use for switching between PO and IV forms

Methadone and Transdermal Fentanyl require unique dosing conversions



For Adult and pediatric patients taking opiouds or doses not listed in Table D, use the following methodology
 * 1) Calculate the previous 24-hour analgesic requirement
 * 2) Convert this amount to the equinalgesic oral morphine dose using Table A
 * 3) Then using Table C, find the correct dose of Fentanyl Patch.

Calculate and recommend an initial starting dose of an opioid to a patient that has developed tolerance to their current opioid therapy. (i.e. take into consideration incomplete cross tolerance)
incomplete cross tolerance refers to an observation that provides rationale for switching to another opioid as a means of restoring analgesic efficacy when the original opioid is not working, as shown by the failure of dose escalation

The new opioid dose is decreased because the patient's tolerance to the second opioid will be lower.
 * 1) The first step in switching form one opioid to another is to calculate the total dose of opioids that a patient is taking (both long and short acting) used in a 24 hour period
 * 2) Use an equianalgesic-dose table to estiame the daily dose of the new agent
 * 3) The dosing interval is then determined by the formulation of the new drug (immediate release versus slow release)
 * 4) Because wide ranges in individual responses to the various opioids have been noted, the calculated dose of the new drug should typically be reduced by at lesat 25-50% to ensure safety.
 * 5) The new opioid dose may then be titrated to an appropriate response

Recommend an appropriate opioid for a patient that has an allergic reaction to another opioid
Allergic Drug Class Considerations
 * Allergic cross-reactivity is more likely to occur within each class and less likely with a drug from another analogue class.
 * Naturally occuring and semisynthetic compounds are the most potent histamine releasers
 * The presence of a 6-hydroxyl group may cause erythema and fever

Discuss the practicality and rationale for the use of PCA pumps


Patient Controlled Analgesia - PCA is a technique where patients self-adminsiter narcotics by using a preprogrammed mechanical infusion device that delivers drug via IV or subcutaneous needle or catheter

The controller is preprogrammed to establish "lock out" periods that prevent the pump from delivering a dose if the patient presses the button too often

Most postoperative patients require a basal continuous infusion of opioid in addition to intermittent boluses during the first 24 hour period

The need for continuous basal infusion usually diminishes after 24-48 hours

PCA is most useful in the first 3 to 5 days postoperative when the patient has the most severe pain.

Understand why stimulant laxatives may be needed for patients recieving opioid therapy.
Constipation

Recognize the signs and symptoms of opioid withdrawal
Unlike withdrawal from alcohol or benzodiazepines, opioid withdrawal is not life threatening.

Emergence of withdrawal symptoms varies with half-life of the particular opioid; within 6-12 hours after the last dose of morphine/hydromorphone/oxycodone or 72-96 hours following methadone. Duration and intensity of withdrawal symptoms can be variable and are related to clearance of the drug; withdrawal from morphine is short (5-10 days) but more protracted with methadone.

Symptoms of withdrawal from opiates include, but are not limited to, depression, anxiety, panic attacks, leg cramps, abdominal cramps, vomiting, diarrhea, insomnia, and cravings for the drug itself.

Additional withdrawal symptoms include, but are not limited to, rhinitis (irritation and inflammation of the nose), lacrimation (tearing), severe fatigue, lack of motivation, moderate to severe and crushing depression, feelings of panic, sensations in the legs (and occasionally arms) causing kicking movements which disrupt sleep, chills, gooseflesh, headaches, anorexia (lack of appetite), benign fasciculation syndrome, mild or moderate tremors, and other adrenergic symptoms, severe aches and pains in muscles and perceivably bones, and weight loss in severe withdrawal.

Neuropathic Pain
Diabetic peripheral neuropathy is one of the most common symptomatic, long term complications in patients with both Type 1 and Type 2 diabetes mellitus. It is also a complication of HIV infection and antiretroviral therapy. It originates from direct injury to a nerve and is often described as having the symtpoms of: Treatment of neuropathic pain is often challenging and may require interdisciplinary participation. Pharmacotherapy includes:
 * Burning
 * Tingling
 * Electric Shock-like
 * Shooting
 * Radiating
 * Stabbing
 * Pins and Needles
 * Tricyclic antidepressants (TCAs) - Amitryptaline (Elavil)
 * Associated with anticholingergic side effects including: constipation, dry mouth, blurred vision, sedation, orthostatic hypotension, urinary retention.
 * Anticonvulsants: Gabapentin (Neurontin) & Pregabalin (Lyrica)
 * Gabapentin - is FDA approved for postherpetic neuralgia & used off label for diabetic neuropathy
 * Pregabalin - is approved for the treatment of neuropathic pain associated with postherpetic neuralgia and diabetic peripheral neuropathy
 * Structural analogs of Gamma-Amino-Butyric-Acid (GABA)
 * also approved for adjuctive therapy of partiel onset seizures in adults with epilepsy
 * Dose: 75mg twice a day
 * Schedule V drug classification
 * Other agents in this class include Carbamepazine, Valproate, Lamotrigine
 * Tramadol (Ultram) & Tramadol/Acetaminophen (Ultracet)
 * Act as an analgesic by mu opioid receptor agonism and weak inhibition of serotonin & norepinephrine
 * watch for drug-drug interactions with anticonvulsants, SSRIs, TCAs,
 * recommended for those unable to tolerate gabapentin or anticonvulsants
 * Opioids
 * There has been much controversy on the appropriate use of opiate therapy in neuropathic pain
 * In the late 1980s and 1990s, it was thought that enuropathic pain was unresponsive to opiate therapy
 * Later, well controlled trials demonstrated that patients with a viarety of neuropathic pain disorders would respont to opiate therapy if dosed appropriately
 * Selective Serotonin and Norepinephrine Reuptake Inhibitor: Duloextine (Cymbalta)
 * The first drug specifically approved for this indication on 09/07/04
 * Recommended NOT to be given in patients with creatinine clearance <30ml/min
 * Doses higher than 60mg per day increase adverse effects without significant icnrease in analgesia.
 * Venlafaxine (effexor)
 * Lidocaine Patch 5%
 * May apply up to 3 patches Topically at one time for up to 12 hours
 * Only approved for postherpetic neuralgia
 * blocks initiation and conduction of nerve impulses

===For medications discussed in this section, know brand and generic names, therapeutic use, usual starting doses, monitoring parameters, common and/or clinically significant side effects, drug interactions, and key points of patient education for the following drugs=== (Since these drugs are largely similar and Dr. Ramsey asked us not to memorize doses, these will be filled in at a later date)

acetaminophen - Tylenol

 * Therapeutic use - Analgesic
 * Usual starting doses - 325 - 625 mg q4-6h
 * Monitoring parameters - not more than 2.6g/day
 * Side effects - Smoking of cigarettes
 * Drug interactions - L.S.D
 * Key Points in patient Education -

tramadol

 * Therapeutic use -
 * Usual starting doses -
 * Monitoring parameters -
 * Side effects -
 * Drug interactions -
 * Key Points in patient Education -

hydrocodone

 * Therapeutic use -
 * Usual starting doses -
 * Monitoring parameters -
 * Side effects -
 * Drug interactions -
 * Key Points in patient Education -

propoxyphene

 * Therapeutic use -
 * Usual starting doses -
 * Monitoring parameters -
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 * Key Points in patient Education -

morphine

 * Therapeutic use -
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oxycodone

 * Therapeutic use -
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methadone

 * Therapeutic use -
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 * Key Points in patient Education -

fentanyl

 * Therapeutic use -
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meperidine

 * Therapeutic use -
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oxymorphone

 * Therapeutic use -
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buprenorphine

 * Therapeutic use -
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gabapentin

 * Therapeutic use -
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pregabalin

 * Therapeutic use -
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duloxetine

 * Therapeutic use -
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milnacipran

 * Therapeutic use -
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cyclobenzaprine

 * Therapeutic use -
 * Usual starting doses -
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 * Key Points in patient Education -

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