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Introduction to Non-Opioid and Opioid Pain Therapy

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1 Introduction to Non-Opioid and Opioid Pain Therapy
Developed by: Jillian Baer, PharmD, BCPS Updated by: Jennifer L. Johansen, PharmD, BCPS Sr. Manager, Drug Information Welcome to our clinical educational program, “Introduction to non-opioid and opioid pain therapy” Presented by: Steve Gilbert, BSc, MBA, CGP, BCPS Director, Clinical Support

2 Disclaimer Statements
This presentation is for educational purposes only. It is not intended as legal or professional advice. Any reproduction by Third Parties of this presentation or materials contained herein is prohibited in the absence of written permission obtained from the author. Review or discussion of any agent does not alter in any way the conditions for use contractually agreed upon and outlined in the Hospice Pharmacia Medication Use Guidelines. This presentation is for educational purposes only. It is not intended as legal or professional advice. The authors have expressly allowed excelleRx and its team members to present this material for educational purposes only. Any reproduction by Third Parties of this presentation or materials contained herein is prohibited in the absence of written permission obtained from the author. This presentation is the intellectual property of Hospice Pharmacia. As an employee of HP, I have been provided permission to share this presentation and material with you today. You may not reproduce this presentation or the material contained herein without the express written permission of Jennifer Johansen. You may contact her at excelleRx. excelleRx, Inc. All Rights Reserved. 2012

3 excelleRx, Inc. All Rights Reserved. 2012
Provider approved by the California Board of Registered Nursing, Provider Number CEP for 1.0 contact hours Release date: 11/28/2012; Expiration date: 11/28/2013 This program was developed for the beginner to advanced nurse working in the hospice and/or palliative care environments. Requirements for statement of credit: Listen to entire presentation; Complete and submit post-test via Xeris with a passing score of at least 70%. Statements of credit: Awarded and sent via , within 4 weeks after receipt of post-test This program may contain content that discusses the off-label use of various medications The program developer/presenter declare no conflicts of interest or relevant financial relationships No financial support was obtained or provided for any component of the educational activity from any commercial interest or any other organization. There are no registration fees. There is a small, processing fee of $11 to be accessed per statement of credit issued to hospice partner participants and will appear on the hospice organization’s monthly bill. excelleRx, Inc. All Rights Reserved. 2012

4 excelleRx, Inc. All Rights Reserved. 2012
Learning Objectives Describe how pain is classified Discuss and perform a proper pain assessment Recognize the differences between the various common non-opioid and opioid therapies used in pain management Recommend appropriate non-opioid and opioid pain therapies After this presentation, participants will be able to: 1. Describe how pain is classified 2. Discuss and perform a proper pain assessment 3. Recognize the differences between the various common opioid therapies used in pain management 4. Discuss the common opioid related adverse effects and the management of these maladies. 5. Recommend appropriate non-opioid and opioid pain therapies excelleRx, Inc. All Rights Reserved. 2012

5 excelleRx, Inc. All Rights Reserved. 2012
Why this topic? > 50 million Americans suffer from chronic pain, and ~25 million Americans experience acute pain each year due to injuries or surgery ~70% of patients w/cancer experience significant pain during their illness, yet < 1/2 receive adequate pain treatment. ~50% of all hospitalized patients have moderate to severe pain in their last days of life. > 20% of Americans aged 60 and over have chronic pain due to arthritis, other joint pain or back pain.   As this slide demonstrate, pain is an all too common symptom and its management can be complex. Not only can a patient’s primary diagnosis cause pain (i.e. cancer), but also common, non-life threatening diseases can also cause pain at the end of life, such as arthritis and other joint disorders. > 50 million Americans suffer from chronic pain, and ~25 million Americans experience acute pain each year due to injuries or surgery ~70% of patients w/cancer experience significant pain during their illness, yet < 1/2 receive adequate pain treatment. ~50% of all hospitalized patients have moderate to severe pain in their last days of life. > 20% of Americans aged 60 and over have chronic pain due to arthritis, other joint pain or back pain.   National Pain Survey, Conducted for Ortho-McNeil Pharmaceutical,1999 Stuart Grossman et al, “Correlation of patient and caregiver ratings of cancer pain.” Journal of Pain and Symptom Management 1991 (6:2) 53ff.; Jamie H. Von Roenn, et al, “Physician Attitudes and Practice in Cancer Pain Management.” Annals of Internal Medicine 15 July 1993 (119:2) 121ff SUPPORT investigators, “A controlled trial to improve the care for seriously ill hospitalized patients.” Journal of the American Medical Association 1995 (274): 1591ff excelleRx, Inc. All Rights Reserved. 2012

6 killed any one. True or False?
Pain never killed any one. True or False? False! Unrelieved pain may be dangerous and is unacceptable. Research shows that postoperative pain can kill by delaying healing and contributing to complications that can be life-threatening. Chronic pain also has many serious adverse effects, that we will discuss in detail later. Post-op pain can delay healing and contribute to complications that may be life-threatening excelleRx, Inc. All Rights Reserved. 2012

7 excelleRx, Inc. All Rights Reserved. 2012
Pain An unpleasant sensory and emotional experience associated with actual or potential tissue damage (APS, 1992) Whatever the patient says it is! (McCaffery, 1968) Impacts psychosocial and physical functioning The American Pain Society defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage.” Pain is a complex phenomenon that can impact a person’s psychosocial and physical functioning. In fact, there is no predictable relationship between identifiable tissue injury and the sensation of pain. For example, a patient under situations of high stress or trauma may describe the pain as being less severe than expected, whereas someone who has chronic pain with little to no identifiable tissue damage may describe pain as being more severe than expected. excelleRx, Inc. All Rights Reserved. 2012

8 Classification of Pain: Chronic vs. Acute
Characteristic Acute Pain Chronic Pain Temporal Recent onset, expected to last no longer than days or weeks; generally follows tissue injury and resolves with healing Remote, often ill-defined onset Intensity Variable Associated Effect Anxiety if pain is severe or cause unknown; sometimes irritability Irritability or depression Associated behaviors Pain behaviors (e.g. moaning, rubbing, splinting) may be prominent when pain is severe May or may not give any indication of pain; specific behaviors (e.g., assuming a comfortable position may occur) Associated Features Sympathetic hyperactivity if severe pain (e.g., tachycardia, hypertension, sweating, mydriasis) May or may not have vegetative signs such as: lassitude, anorexia, weight loss, insomnia, loss of libido Acute pain is well-defined, time-limited and usually a direct result of injury or illness-such as a cut or burn. Chronic pain on the other hand, is less well-defined. To classify pain as “chronic”, it should be persistent for a duration of a few months to 6 months or longer and it usually doesn’t resolve spontaneously. excelleRx, Inc. All Rights Reserved. 2012

9 Classification of Pain: Incident vs. Breakthrough
Precipitated by movement or procedures Breakthrough Between regularly scheduled doses of pain medication Incident pain is pain that is precipitated by movement or procedures such as bathing or when changing wound dressings. Lastly, breakthrough pain is pain that occurs between regularly scheduled doses of pain medication. It is important to recognize the differences between incident pain and breakthrough pain because incident pain can be predicted in most circumstances, thus it can also be prevented whereas breakthrough pain isn’t as predictable. excelleRx, Inc. All Rights Reserved. 2012

10 Classification of Pain: Nociceptive vs. Neuropathic
There are two main types of pain: “nociceptive” and “neuropathic.” Nociceptive pain arises through normal processing of stimuli that damages normal tissues, or has the potential to do so if the stimuli is prolonged. This type of pain is usually responsive to both non-opioid analgesics and opioids. Neuropathic pain on the other hand results from abnormal processing of sensory input by the peripheral or central nervous system. This type of pain also responds to opioids, but often times, patients need adjuvant medications to fully control their pain. excelleRx, Inc. All Rights Reserved. 2012

11 Nociceptive Pain: Somatic Pain
Arises from bone, joint, muscle, skin, or connective tissue Described as: aching, throbbing, sharp, worsens with movement Well localized Examples: muscle spasm, bone metastases, incisions, tumor invasion into surrounding tissue, broken bone. Somatic pain is a sub-type of nociceptive pain and is the most common type of pain. It arises from receptors in the bone, joints, muscle, skin, or connective tissue. Patients frequently describe this as aching or throbbing pain that may worsen with movement. It is usually well localized, as patients can often times point to the location of pain with one finger. Examples of this include bone pain from a bone break or incision pain from an operation. excelleRx, Inc. All Rights Reserved. 2012

12 Nociceptive Pain: Visceral Pain
Stretching or distention of pelvic, thoracic, or abdominal viscera Described as: deep, squeezing, pressure Often poorly localized, may be referred along a dermatome Examples: Myocardial infarction, hepatic metastases, bowel obstruction The second subtype of pain is visceral pain. This type of pain originates from the visceral organs which includes the stomach, intestines, liver and pancreas. It is frequently described by patients as being deep, squeezing, cramping, pressure-like. It is often poorly localized, patients will not be able to directly point to the location of the pain, they may need to use their entire hand to describe the feeling or location of the pain. Sometimes, this type of pain may be associated with nausea, vomiting and sweating. excelleRx, Inc. All Rights Reserved. 2012

13 excelleRx, Inc. All Rights Reserved. 2012
Neuropathic Pain Pain reports may be disproportionate to physical findings Serves no protective function Described as: sharp, shooting, tingling, stabbing, electric, numbness, burning Examples: spinal cord compression, shingles, peripheral neuropathy Patients who experience neuropathic pains may describe this pain as “sharp, shooting, tingling, numbing, electric and/or stabbing”. There are many reasons why a patient may experience nerve pains…some examples include spinal cord compression, shingles, or peripheral neuropathy. Neuropathic pain can be caused by a dysfunction of the central and/or peripheral nervous system or a primary lesion in that area. Some suggestions as to the potential cause of neuropathic pain includes nerve trauma, infection such as from shingles, pressure from tumor infiltration, infarction, metabolic imbalance such as from diabetic neuropathy or it may just be idiopathic, meaning so specific cause exists or can be determined. excelleRx, Inc. All Rights Reserved. 2012

14 excelleRx, Inc. All Rights Reserved. 2012
Unrelieved pain can have a number of harmful effects on patients beyond just causing physical discomfort. A full discussion on the effect of pain on each of these domains is outside the scope of this program however in general, pain can have effects in almost every system within the body and of course their quality of life. (McCaffery, 1999) excelleRx, Inc. All Rights Reserved. 2012

15 Unassessed pain = Untreated Pain
Physical Fatigue, decreased activity Nausea Insomnia Poor appetite Psychological Depression Anxiety Anger, irritability, agitation Loss of control Decreased cognition What happens if we do not assess pain? It can go untreated all together or it can be mistreated because we do not know the likely etiology. As a result the patient can suffer both physically and psychologically. excelleRx, Inc. All Rights Reserved. 2012

16 excelleRx, Inc. All Rights Reserved. 2012
Assessment Overview The APS (American Pain Society) calls pain the “5th Vital Sign” Assess when HR, BP, RR & Temp. are measured Goal of initial assessment Characterize pain by location, intensity, etiology Detailed history Physical Exam Psychosocial assessment Diagnostic evaluation Now that we have reviewed how pain is classified, lets review how pain should be assessed. The American Pain Society (APS) calls pain the “5th vital sign” and suggests that pain should be assessed when the heart rate, blood pressure, temperature and respirations are measured. The goal of the initial assessment is to characterize pain by location, intensity and etiology…basically we want to find the cause and type of pain then treat accordingly. Upon the initial assessment we should aim to gather a detailed history, conduct a physical examination and psychosocial assessment as well as a diagnostic evaluation excelleRx, Inc. All Rights Reserved. 2012

17 When Should Assessment Occur?
Upon admission To identify a pain problem Establish a baseline/history Serve as a guide for care/treatment At regular, ongoing intervals after starting treatment With each new report of pain At appropriate intervals after intervention (i.e hours after fentanyl patch initiation) KEY: know the onset of action and peak effect of the medication Besides performing an assessment on the initial visit, pain assessments should also occur: At regular intervals after starting treatment With each new report of pain And at appropriate intervals after intervention…for example, if you started a patient on Duragesic®, you would want to assess their pain about 12 to 18 hours after applying the patch due to the onset and peak effect of the drug. So the key is knowing the onset of action and peak effect of the medication. excelleRx, Inc. All Rights Reserved. 2012

18 Elements of a Comprehensive Pain Assessment
Complete History Physical Exam Laboratory and Radiologic Tests A comprehensive pain assessment looks at these three areas: complete history, physical exam, and laboratory/radiologic tests – however we are going to focus on the complete history today. excelleRx, Inc. All Rights Reserved. 2012

19 “PQRSTU” Pain Assessment Mnemonic
P: Palliating/Precipitating factors What makes your pain better? Worse? Movement? Hygiene care? Q: Quality Describe your pain for me? R: Radiation or pattern Does the pain move from one place to another or does it stay in one place? Where? S: Severity or site On a scale of 0-10 with 0=no pain and 10=worse pain possible, where is your pain now? At its worst? At its best? After you take pain medication? T: Temporal nature Is your pain constant or intermittent? How long have you had this pain? U. YOU! What are your pain management goals including intensity, QOL and activity level? What does your pain mean to you? In regards to assessing pain, many tools have evolved to help medical professionals understand and perform proper pain assessments. One of these tools is an alphabetical mnemonic “PQRTSU” P = Palliating and/or Precipitating factors What makes your pain better? What makes your pain worse? Is the pain associated with movement or hygiene care? Q = Quality Can you describe your pain for me? Is it throbbing and sharp or numb and tingling? R = Radiation Does the pain move from one place to another or does it stay in one place? Where is it located? S = Severity On a scale of 0 to 10 with 0=no pain and 10=worse pain possible, how is your pain now? How is it at its worst? How is it at its best? How about after you take pain medication? T = Temporal nature. Is your pain constant or intermittent? How long have you had this pain? U = YOU! What are your pain management goals including intensity, QOL and activity level? What does your pain mean to you? excelleRx, Inc. All Rights Reserved. 2012

20 Pain Assessment Scales
Simple Descriptive Pain Distress Scale [1] None Annoying Uncomfortable Dreadful Horrible Agonizing |___________|___________|____________|__________|___________| 0-10 Numeric Pain Distress Scale [1] No Distressing Unbearable pain pain pain |_____|_____|_____|_____|_____|_____|_____|_____|_____|_____| Visual Analog Scale (VAS) [2] No Unbearable distress distress |___________________________________________________________| Another tool used for assessing pain are pain assessment scales. These scales for helpful for recognizing, standardizing, and evaluating treatments. Some scales that are used include the simple descriptive pain distress scale, the numeric pain distress scale, the visual analog scale or the Faces scale which is especially good for children, non-English speaking patients or those that are cognitively impaired. Once a scale is chosen – use it consistently! There is less confusion for patient, caregiver, and clinician and allows for comparable results between ratings. Wong-Baker FACES Pain Rating Scale excelleRx, Inc. All Rights Reserved. 2012

21 Patients at Risk for Poor Assessment
Children Elderly Cognitively impaired persons/unconscious Non-English speaking Substance abuse history Despite our best efforts to gather essential information for a pain assessment, there are patients who may be considered “at risk” for poor assessments and management. These patients may be: children, the elderly, cognitively impaired or unconscious persons, non-English speaking patients or patients from different cultural backgrounds and in patients with substance abuse history. excelleRx, Inc. All Rights Reserved. 2012

22 Pain Assessment in Special Populations: Impaired Cognition
Common finding in hospice patients Difficulty due to decreased memory, poor orientation, visual, and spatial skills excelleRx, Inc. All Rights Reserved. 2012

23 excelleRx, Inc. All Rights Reserved. 2012
Pain Assessment in Special Populations: Impaired Cognition - Suggestions May need to repeat the scale more than once and give sufficient time for an answer Scale of 0-5 may be easier to use than 0-10 scale May require assessment by third party in nonverbal patients Need to use behavioral cues: Facial expressions Muscle tension Gestures Look over a 5-minute period for frequency, intensity, and duration to rule out transitory, meaningless gestures CNPI (Checklist of Non-verbal Pain Indicators – easy to use and score – 6 behaviors) was found to have good face validity and interrater reliability of 93% among hip fracture patients who are 60 and 40% cognitively intact excelleRx, Inc. All Rights Reserved. 2012

24 excelleRx, Inc. All Rights Reserved. 2012
Pop Quiz! Andrew is 25 years old and this is his first day after abdominal surgery. As you enter the room, he smiles at you and continues talking and joking with his visitor. Your assessment reveals the following information: BP: 120/80 HR: 80 RR: 18 On a scale of 0-10 (0 = no pain, 10 = worst pain), he rates his pain as an 8. On the patient’s record you must mark his pain on the scale below. What is the number that represents your assessment of Andrew’s pain? No pain Worst pain excelleRx, Inc. All Rights Reserved. 2012

25 Assessment Clinical Pearls
Patient knows best – only the patient can describe and rate the pain! Choose the appropriate tool given the patient’s clinical status Once the appropriate tool has been selected, use it consistently with that patient to enable symptom tracking PQRSTU can be used for any patient complaint! excelleRx, Inc. All Rights Reserved. 2012

26 excelleRx, Inc. All Rights Reserved. 2012
Medication Therapy Let’s move on to discussing treatment options for the management of pain but first I’d like to go over basic pain management standards. excelleRx, Inc. All Rights Reserved. 2012

27 Drug Therapy: Overview of Pain Management Standards
Right drug, right dose, right route, right schedule Start with minimal effective dose Reassess frequently Constant pain needs around-the-clock dosing AND breakthrough Plan/monitor for side effects & treat accordingly Use non-pharmacological therapies when appropriate Provide education Adjuvants for specific pain (ex. bone, neuropathic) This slide highlights the basic standards in regards to pain management. These standards include: Remember the 4 “rights”: the right drug, the right dose, the right route, and the right schedule that’s best appropriate for the patient. Start with the minimal effective dose and titrate up as necessary Reassess pain frequently, especially in early therapy and titrate as needed to achieve adequate pain relief If pain is constant, switch to around-the-clock dosing and always include breakthrough pain medications ---Don’t forget to medicate for incident pain—i.e. prior to wound care or movement Plan and monitor for side effects and treat accordingly. For example, when starting a patient on an opioid also start the patient on a bowel regimen to handle opioid induced constipation. Use non-pharmacological therapies when appropriate Provide education to patient, family and caregiver about medication risks and benefits Use adjuvants for specific pain syndromes (i.e. neuropathic, bone, visceral) excelleRx, Inc. All Rights Reserved. 2012

28 World Health Organization Approach
By the mouth Use oral route & least invasive route whenever possible By the clock Give ATC for constant pain with appropriate breakthrough By the ladder Assess pain severity & treat accordingly For the individual Selection of medication is patient-based With attention to detail Assess pain regularly, adjust ATC based on breakthrough, watch side effects, etc. Let’s briefly look at the World Health Organization’s (WHO) approach to drug management of cancer pain. You can remember the WHO approach by remembering: By the mouth, by the clock, by the ladder, for the individual and with attention to detail. By the mouth meaning try to use the oral route and least invasive routes of administration whenever possible. By the clock meaning give medications around the clock if pain is constant and provide the patient with appropriate medication for breakthrough and/or incident pain By the ladder meaning to assess pain severity and treat accordingly. For example, if a patient is rating their pain a 9 out of 10, we would want to select a pain medication indicated for severe pain. For the individual means that medication selection is based on patient specific factors such as the quality and cause of the pain, the patient’s age, kidney/liver function, etc. Finally, with attention to detail means to assess pain regularly, adjust ATC dosing as necessary, watch for and treat side effects, and treat conditions that may exacerbate pain such as depression, anxiety, insomnia, infection and others. excelleRx, Inc. All Rights Reserved. 2012

29 Pain Treatment Options
Non-pharmacologic Heat/cold therapy Massage Physical/Occupational therapy Aromatherapy Music therapy Spiritual/Religious counseling Pharmacologic Non-opioids Opioids Adjuvants Traditionally, pharmacological agents are employed to treat pain, however, we should also be aware of and recognize that there are a number of non-pharmacologic methods that can help reduce pain. These methods may include: heat or cold therapy, massage, physical or occupational therapy, aromatherapy, music therapy, and spiritual or religious counseling. These treatments may be used alone if effective or they may be used to compliment pharmacological treatments. The pharmacological agents used in pain management can generally be divided into 3 categories: the non-opioids, the opioids and adjuvant medications. Due to time constraints, adjuvants will not be discussed in detail during today’s educational session…our focus will be contained to non-opioids and opioids, however, please stay tuned to next quarter in May, where adjuvants will be discussed in more detail. excelleRx, Inc. All Rights Reserved. 2012

30 FALSE…depends on the type of pain!
Pop Quiz! True or False? Non-opioids are not useful analgesics for severe pain. FALSE…depends on the type of pain! excelleRx, Inc. All Rights Reserved. 2012

31 excelleRx, Inc. All Rights Reserved. 2012
Non-opioids Acetaminophen (Tylenol®) NSAIDS (Non-steroidal anti-inflammatory drugs) Corticosteroids (Decadron®, Prednisone®) The non-opioid group generally consists of acetaminophen, NSAIDS, and corticosteroids. excelleRx, Inc. All Rights Reserved. 2012

32 Acetaminophen (Tylenol®)
Mild musculoskeletal pains (osteoarthritis); Fever No anti-inflammatory effects Ceiling effect Fewer adverse effects No risk for GI bleeding Liver toxicity (>4gm/day) Elderly/patients with liver disease should use  3gm/day Inc. risk with underlying liver disease or chronic alcoholism Acetaminophen or (APAP) can be used for the management of mild musculoskeletal pains such as those seen associated with osteoarthritis and it also frequently used to treat patients with fever. Acetaminophen has no effect on inflammation. It works by inhibiting the production of prostaglandins and blocking peripheral impulse generation both of which contribute to pain. However, there is a ceiling effect associated with acetaminophen. This means that increasing the dose beyond a certain point will not increase the analgesic effect but may increase the risk for side effects. On the other hand and unlike the NSAID class, there is no risk for GI bleeding and generally has fewer adverse effects compared to other non-opioid analgesics. Kidney and liver toxicity may be seen, especially in those patients with impairments to the kidney or liver and this occurs due to accumulation of the toxic metabolite. Because of this concern, it is recommended that those patients at risk for hepatotoxicity (such as those with chronic alcoholism) should avoid doses that exceed 4gm/day whereas the elderly and those with established liver disease should use a daily dose of 3gm or less. excelleRx, Inc. All Rights Reserved. 2012

33 excelleRx, Inc. All Rights Reserved. 2012
NSAIDS Mild-moderate inflammation related pain; Fever Bone metastasis, arthritis, soft-tissue infiltration, recent surgery Can enhance opioid-based analgesia When inflammation is causing pain, addition of NSAID will often reduce opioid requirements and provide better pain relief Combination of multiple NSAIDS not recommended No evidence to suggest improved levels of analgesia Increased risk for adverse effects and drug interactions Ceiling effect The NSAID class can be used to treat mild to moderate pain especially if inflammation is involved as well as fever. NSAIDS may be especially useful for those patients who have an inflammatory component to their pain. Examples of these include: bone metastases, arthritis, soft-tissue infiltration and recent surgery. NSAIDS may also enhance opioid analgesia due to their different mechanism of action. Like acetaminophen, the NSAIDS also have a ceiling effect associated with their use. excelleRx, Inc. All Rights Reserved. 2012

34 NSAIDS Adverse Effects
GI toxicity Reduced by adding a proton pump inhibitor, H2 antagonist, misoprostol Kidney dysfunction Inc. risk if patient dehydrated; Altered kidney blood flow Confusion Fluid retention May exacerbate heart failure & hypertension Salicylism Ringing in ears (tinnitus), nausea, vomiting Platelet dysfunction Reversed by stopping NSAID Stop Aspirin therapy 7 days prior to invasive procedure Adverse effects that may be seen with NSAID use includes: GI toxicity (especially with aspirin or the other salicylates). This can be reduced by adding a proton pump inhibitor (Ex. Prilosec), an H2 antagonist (ex. Zantac) or misoprostol (Cytotec) Kidney dysfunction, although not common, can occur and the risk is increased in a dehydrated patient. This is because NSAIDS can alter kidney blood flow which leads to decreased urine output and eventually kidney impairment. Fluid retention can occur so caution needs to be exercised in those patients with cardiac issues such as congestive heart failure and hypertension. Salicylism may occur which is characterized by tinnitus or ringing in the ears, nausea and vomiting. This effect may be more of a concern with aspirin and it’s derivatives. Other effects include confusion as well as platelet dysfunction which can be reversed by stopping the NSAID (For those patients undergoing an invasive procedure, aspirin must be stopped at least 7 days prior to that procedure) All of the NSAIDS, including the COX-2 inhibitors can decrease renal blood flow and cause fluid retention, hypertension, and renal failure, especially in the elderly and those on diuretic therapy. excelleRx, Inc. All Rights Reserved. 2012

35 Corticosteroids: Place in Therapy
Reduces cerebral and spinal cord edema/compression Reduces edema in other areas: Rectal/cervical tumor affecting sacral area Reduces capsular stretch in liver, spleen, lymph nodes and adrenal glands causing visceral distention Stimulates appetite; creates feeling of well-being (euphoria) Effective for bone pain if inflammation is involved Overall effects: Mood elevation, anti-inflammatory, anti-emetic, euphoria, appetite stimulation, increased weight Corticosteroids are very useful in managing pain as well as other symptoms in hospice patients. They can help manage neuropathic pain by reducing spinal cord compression and inflammation. They also reduce cerebral edema and in addition, they help to reduce edema and inflammation in others areas such as in the sacral area affected by rectal, cervical and other genitourinary tumors as well as in the bone. Corticosteroids are used to manage visceral pain by reducing visceral distention that may occur from capsular stretch in liver, spleen, lymph nodes and adrenal glands. Examples of where you may see corticosteroids being used to manage visceral pain includes liver cancer, hepatitis, and pancreatic cancer. Corticosteroids are frequently employed to manage bone pain especially if inflammation is associated with the pain. As mentioned previously, the corticosteroids have the potential to produce some unwanted side effects, however, they also possess properties that a hospice patient may find beneficial such as mood elevation, anti-emetic activity, improved well being and appetite stimulation. excelleRx, Inc. All Rights Reserved. 2012

36 Corticosteroids: Potency
Drug Equal Dose Anti-inflammatory Potency Sodium-Retaining Potency Cortisone 25 mg 0.8 Dexamethasone 0.75 mg 25 Hydrocortisone 20 mg 1 Methylprednisolone 4mg 5 0.5 Prednisone 5mg 4 In regards to the anti-inflammatory potency of these agents, dexamethasone is about 5 to 7 times stronger than prednisone and 4 to 6 times stronger than methylprednisolone. This translates to a dose of 5mg of Prednisone = 4mg of methylprednisolone = 0.75mg of dexamethasone. Dexamethasone produces the least amount of mineralocorticoid effect, with the highest amount of anti-inflammatory effect! excelleRx, Inc. All Rights Reserved. 2012

37 Corticosteroids: Adverse Effects
Key Adverse Effects: Insomnia/nervousness - Give last dose no later than 2-3pm in order to minimize insomnia Hyperglycemic effects – Monitor patients with diabetes for changes in glucose control Edema, facial hair growth (with long term use) Weigh risks vs. benefits for use in patients with relative contraindications e.g. Diabetes; immunosuppression – What is more important at this point? The more common side effects that we see with corticosteroid use include insomnia, nervousness, indigestion and increased appetite. To minimize the effects on sleep, it is suggested to take the last dose of the corticosteroid no later than 2 or 3pm. It is also recommended to weigh the risks versus the benefits for use in patients with relative contraindications. For example, if a patient has diabetes, corticosteroids can still be used safely and effectively. Consider what is more important and what would provide better symptoms management for the patient – management of the pain or avoiding changes in blood sugar? excelleRx, Inc. All Rights Reserved. 2012

38 excelleRx, Inc. All Rights Reserved. 2012
Case Discussion GB is a 68-year-old male with a primary diagnosis of heart failure. His past medical history is significant for a seizure disorder, hypertension, and depression. He is complaining of generalized pain and his nurse would like to get a pharmacist recommendation. Current medications: Lisinopril 20mg PO QD Metoprolol 50 mg PO BID Digoxin 0.125mg PO QD Furosemide 80mg PO QAM K-Dur 20 mEq PO QD Fluoxetine 20mg QD Loperamide 2-mg after each loose stool Allergies: Sulfa drugs Assessment results: P: Constant; worsens with movement; Aspercreme & heating pad Q: Achy R: Stays over joints; no radiation S: Almost all joints; Rates as 1-2/10; will increase to 3-4/10 with movement T: Occurs at rest, at night, and w/ movement. U: Stiffness in knees/hips in the AM, but decreases after dressing. Denies fatigue, weakness, and joint redness/swelling What agent would you recommend to treat this patient’s complaint and why? Pharmacist Recommendation: Acetaminophen 650mg PO q4-6H ATC Recommendation Reasoning: Patient is complaining of what sounds like osteoarthritis due to his complaint of stiffness in large joints upon wakening, pain associated with movement, and the absence of inflammatory signs or symptoms. The drug of choice for osteoarthritis is acetaminophen; however if this does not adequately relieve the patient’s pain, then a low dose opioid would also be an appropriate choice. If an opioid is chosen, a low dose should be initiated because this man is opioid naïve. An NSAID or a COX-2 selective agent would not be appropriate in this patient due to his history of CHF, as this could worsen fluid retention. Furthermore the patient is not describing an inflammatory process as he denied the presence of any redness or swelling, therefore there is not indication for an agent with anti-inflammatory type properties. Learning Points: Recognition of somatic pain Use of acetaminophen in the treatment of bone pain or opioid agent vs. NSAID Risks of using an NSAID in this patient: Exacerbation of CHF excelleRx, Inc. All Rights Reserved. 2012

39 excelleRx, Inc. All Rights Reserved. 2012
Opioids Pain relief through binding to mu, kappa, & delta receptors In brain & spinal cord Binding prevents release of certain neurotransmitters involved in transmission of pain Mu Analgesia, resp. depression, pupil constriction, euphoria, reduced GI motility Kappa Analgesia, resp. depression, pupil constriction, dysphoria, psychomimetic effects Delta Analgesia Pain relief from opioids is mediated through binding to (mu, kappa, and delta) receptors that are located in the brain and spinal cord to prevent the release of certain neurotransmitters that are involved in the transmission of pain. Specifically, binding to the mu receptors produces analgesia, respiratory depression, pupil constriction, euphoria and decreased GI motility. Binding to the kappa receptors will produce analgesia, respiratory depression, pupil constriction, dysphoria and psychomimetic effects And binding to the delta receptors will produce analgesia only. excelleRx, Inc. All Rights Reserved. 2012

40 excelleRx, Inc. All Rights Reserved. 2012
Types of Opioids Opioid Agonists Codeine Hydrocodone Oxycodone Meperidine Propoxyphene Fentanyl Hydromorphone Oxymorphone Morphine Opioid Agonists/NMDA Receptor Antagonists Levorphanol Methadone Opioid Agonist/ Norepinephrine Reuptake Inhibitors Tapentadol Tramadol Mixed Opioid Agonist/Antagonists Butorphanol Morphine/Naltrexone Pentazocine Buprenorphine Nalbuphine Antagonists Naloxone Naltrexone This chart shows examples of the different opioid classes. Examples of full agonist opioids include morphine, oxycodone, hydromorphone, and fentanyl. A full agonist is a drug or substance that acts at the receptor site to produce the same or similar effect as the body’s normal chemical messenger. Other medications such as methadone or tapentadol have both opioid agonist properties and additional pain relieving properties such as NMDA receptor antagonism or norepinephrine reuptake inhibition. These additional properties may make these opioids preferred for patients with neuropathic pain or mixed pain types. Some mixed agonist/antagonist drugs include pentazocine (Talwin), butorphanol (Stadol), nalbuphine (Nubain) and/or buprenorphine (Temgesic). A mixed agonist/antagonist is a drug or substance that falls in between a full agonist and antagonist meaning that these drugs are agonists at some opioid receptors and antagonists at others. And 2 examples of opioid antagonists include naloxone and naltrexone. An antagonist is a drug or substance with opposite action to that of another drug or natural body chemical, which it inhibits. The rest of this discussion of opioids will focus on those opioids included in the per diem. excelleRx, Inc. All Rights Reserved. 2012

41 Major Opioid Adverse Effects
Manifestation Mood changes Dysphoria, euphoria Somnolence Lethargy, drowsiness, apathy, inability to concentrate Stimulation of CTZ; Delayed gastric emptying Nausea, vomiting Respiratory depression Decreased respiratory rate Decreased GI motility Constipation Increased sphincter tone Biliary spasm, urinary retention Histamine release Hives, itching, asthma exacerbation (rare) Tolerance Larger doses for same effect Dependence Withdrawal symptoms w/ abrupt d/c Adapted from Dipiro et al. This chart highlights the major opioid adverse effects and the associated manifestations for the side effect. The manifestations highlighted in red italics are the more commonly experienced manifestations. For example, opioids can produce somnolence which can further cause lethargy and drowsiness and stimulation of the chemoreceptors in the brain can induce nausea and vomiting. Other frequent effects from opioids include constipation from decreased GI motility and urinary retention or biliary spasms from increased sphincter tone. excelleRx, Inc. All Rights Reserved. 2012

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Morphine Short-acting (MSIR®, RoxanolTM) Long-acting (MsContin,® Kadian®) “Gold Standard” of opioid agonists - most experience and data Can be administered via many routes, i.e. oral, rectal, sublingual, IV/ IM/SC, epidural/intrathecal Pharmacokinetics: Significantly metabolized in the liver: Morphine 3-glucuronide (toxic) Morphine 6-glucuronide (active, potentially toxic) Bioavailability ~ 40% Hepatic disease/impairment can actually increase bioavailability Eliminated via glomerular filtration (risk in patients with renal dysfunction) excelleRx, Inc. All Rights Reserved. 2012

43 Hydromorphone Short-acting (Dilaudid®)
Alternative to morphine – not superior in efficacy Can be administered via many routes, i.e. oral, rectal, sublingual, IV/ IM/SC, epidural/intrathecal Pharmacokinetics Significantly metabolized in the liver: Hydromorphone 3-glucuronide (toxic) Hydromorphone 6-hydroxy metabolites (active in animals, not in humans) Bioavailability ~ 60% Hepatic disease/impairment can actually increase bioavailability Eliminated via urine primarily as hydromorphone 3-glucuronide (potential for renal accumulation of toxic metabolite) excelleRx, Inc. All Rights Reserved. 2012

44 Oxycodone Short-acting (OXYIR®, Oxyfast®)
Alternative to morphine – not superior in efficacy Routes of administration: oral, rectal (except long-acting) Available in combination with acetaminophen (Percocet®) or aspirin (Percodan®) Pharmacokinetics Oxidized in the liver: Approximately 95% noroxycodone (inactive, questionable toxicity) Approximately 5% oxymorphone (active, twice as potent, accumulates in renal impairment) excelleRx, Inc. All Rights Reserved. 2012

45 Fentanyl Long-acting (Duragesic®)
Alternative to morphine – not superior in efficacy, one study reports less constipating Various routes of administration – transdermal, IV/IM/SC, transmucosal, intranasal, epidural/intrathecal Pharmacokinetics Poor oral bioavailability Metabolized in the liver to inactive metabolites Does not accumulate in renal dysfunction – may be preferred in patients with renal dysfunction excelleRx, Inc. All Rights Reserved. 2012

46 Transdermal Fentanyl (Duragesic)
Rate of drug delivery is not the same on all 3 days Day 1 – concentration gradient jump-started Day 2 – concentration gradient established and starts to slow down Day 3 – concentration gradient reaches equilibrium Significant amount of fentanyl left in patch after dosing interval is complete Never occlude, cut, or “half” patches to titrate dose excelleRx, Inc. All Rights Reserved. 2012

47 Transdermal Fentanyl: Patient Considerations
Patient’s pain is unstable 12-17 hour delay in onset of pain relief for transdermal fentanyl  makes titration difficult in the face of a changing pain picture Secondary diagnoses: DM, PVD, CHD, HTN, etc. Patient’s circulation may not be sufficient to carry fentanyl from the subcutaneous depot to central sites Lean body mass May not be enough subcutaneous fat to allow for a depot Subject to changes in body temperature Changes in skin temperature will change absorption rate of fentanyl Medication Requirement Not for opioid naïve patients. Should only be used in patients who have demonstrated tolerance and who require total daily dose of at least equivalent to transdermal fentanyl 25mcg/hr (i.e. oral morphine of 60mg.day) Doses > mcg/hr are difficult to administer due to limitation of areas to rotate patch application excelleRx, Inc. All Rights Reserved. 2012

48 Methadone (Dolophine®, Methadose®)
Synthetic Opioid Quick onset of action (~30-60 mins) and high bioavailability (~ 80% PO) Long-acting properties naturally The only liquid “long acting” opioid Acute dosing has relatively short half-life Elimination half-life increased with chronic dosing Up to 130 hours Long acting properties start to take effect with chronic use No toxic metabolites No dosage adjustment needed for renal impairment Typical starting dose: 2.5mg-5mg PO q12h or q8h excelleRx, Inc. All Rights Reserved. 2012

49 Methadone: Mechanism of Action
Methadone is a racemic mixture (R+S) S-isomer has neuropathic adjuvant properties NMDA receptor antagonist Can undo “wind up” phenomenon Norepinephrine reuptake inhibitor Serotonin reuptake inhibitor R-isomer has opioid properties Different receptor activity from traditional opioids Greater affinity for delta receptors Very potent analgesic Less affinity for mu receptors Less constipation, hallucinations, euphoria excelleRx, Inc. All Rights Reserved. 2012

50 Potential Situations for Methadone Use for Pain
Morphine Allergy Renal Impairment Neuropathic Pain Opioid Adverse Effects Not swallowing solid dosage forms Refractory Pain Methadone can be considered in patients who have a morphine allergy, significant renal impairment, complex pain that includes neuropathic pain, as a rotation option for those with adverse effects from other opioids or refractory pain, and those that require a long-acting opioid, but need an oral solution instead of a tablet. * Safety tip: It may be helpful to explore the possibility with the pharmacy provider to add a coloring agent to either oral solution when using both methadone concentrate and another opioid concentrate (e.g. morphine 20mg/mL for breakthrough pain), simultaneously. This may help patients and caregivers differentiate between the two and avoid mixing them up, due to their similarity. excelleRx, Inc. All Rights Reserved. 2012 50

51 Methadone…Challenging Situations
Limited Prognosis Multiple Drug Interactions Lives alone, unreliable, poor cognitive functioning Syncope, Arrhythmia, QT Prolonging Drugs While there are many advantages to using methadone, there are also some challenges that may make it inappropriate for some patients. Methadone has a relatively long elimination half-life, with an average of hours. Therefore it can take about 4-10 days to achieve a steady state concentration of methadone in the serum. This makes methadone challenging to use at the end of life, particularly in patients with a limited prognosis. If it is anticipated that the patient has less than 1 week to live, it may be wise to avoid using methadone. The patient might not have enough time to reach steady state and may never realize complete pain control. Methadone’s metabolism is impacted by numerous drugs – leading to either increased or decreased methadone serum levels. If there are multiple drug interactions present, particularly if the interacting medications cannot be switched to an alternative or medications cannot be discontinued, then methadone may not be the best option. Given methadone’s propensity to prolong the QT interval potentially leading to a fatal arrhythmia, it may be wise to avoid using methadone in patients with a history of syncope (which is a symptom of potential ventricular fibrillation), arrhythmias (particular ventricular arrhythmias), or using other QT prolonging medications. Finally, it is important that patients use methadone as prescribed to avoid potential toxicity if the patient lives alone and is unreliable in administering medication or has poor cognitive functioning, methadone may not be appropriate. It is important to remember that none of these characteristics are absolute contraindications for the use of methadone, but they do place the patient at increased risk for toxicity. When considering methadone for a patient, it is important to assess and screen for these issues to make sure that methadone is safe to use. excelleRx, Inc. All Rights Reserved. 2012 51

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Methadone prescribing requires knowledge of its: Unique pharmacodynamic and pharmacokinetic properties Potential for drug interactions and side effects Complex conversion ratios and protocols excelleRx, Inc. All Rights Reserved. 2012

53 Consult with knowledgeable prescriber and/or pharmacist
BEFORE starting therapy with methadone Explain complex dosing and conversion requires expertise excelleRx, Inc. All Rights Reserved. 2012

54 Methadone For… Pain Control vs. Addiction Maintenance
Federal law prohibits pharmacies from dispensing methadone for addiction maintenance There are no limitations for dispensing methadone for pain control Common doses for addiction are high and given once daily excelleRx, Inc. All Rights Reserved. 2012

55 Long-Acting Opioid Cost Considerations
Equianalgesic drug regimen Qty {15 day supply} Approximate cost Exalgo® (Hydromorphone) 32mg daily 15 tablets $$$$$$ Morphine LA tablet 60mg q12h 30 tablets $$$ Kadian ® (LA Morphine capsule) 120mg daily 15 capsules $$$$$ OxyContin® (Oxycodone) 40mg q12h Transdermal Fentanyl 50mcg q72h 5 patches Methadone 5mg q8h 45 tablets $ excelleRx, Inc. All Rights Reserved. 2012

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Case Discussion JW is a 65-year-old male with a primary diagnosis of prostate cancer. He is experiencing generalized pain. He has a history of chronic renal insufficiency, hypertension, and diabetes. He is restricted to a wheel chair secondary to an injury he sustained while enlisted in the military. As a result of his disease process, he has also begun to complain of a loss of appetite leading to weight loss. Current medications include: Insulin glargine 40 units once daily Insulin aspart SSI prior to meals Casodex (Bicalutamide) 150mg PO once daily Amlodipine 5 mg PO once daily Allergies: No known allergies Assessment: P: Woke up with pain one AM & has remained since. Has not tried any medication for the pain. Q: Nagging throb R: Pain does not really go anywhere. S: Located primarily in hips and legs. 2/10 at worst. T: Pain started ~3 days ago and has continued intermittently. Worsens when transferring from wheel chair to bed. U: Has made transferring and requires help of his wife - difficult for her due to decreased strength. She fears that she will be unable to get him in and out of his wheel chair and that he will then become isolated What agent would you choose to treat this patient’s complaint and why? Pharmacist Recommendation: Dexamethasone 4mg PO once daily, titrate as needed Recommendation Reasoning: The pain experienced by this gentleman is somatic type pain, possibly due to bone metastases. The options to treat this type of pain include NSAIDs or corticosteroids. This patient has a history of kidney dysfunction and hypertension therefore making NSAIDs not an optimal choice in this patient. Dexamethasone was chosen because not only will it address his bone pain, but also it will perhaps address his complaint of worsening appetite. Although the dexamethasone may worsen his glucose control, this can be easily addressed through addressing his insulin requirements. Since he is on insulin, he will need to continue to check his blood sugars and monitor for signs and symptoms of hyper and hypoglycemia. However, since he is a hospice patient and has a poor prognosis, stringent monitoring and control of his blood glucose is not necessary. A low dose should be started due to his history of renal disease. Learning Points: Recognition of somatic bone pain and ability to use corticosteroids as a viable option Recognition of dual benefits of dexamethasone and its potential adverse effects Recognition of potential worsening of renal function. excelleRx, Inc. All Rights Reserved. 2012

57 Opioid Combination Products
Takes advantage of central and peripheral mechanisms of action  potentiated analgesic effect Primary limitation: maximum daily dosage of non-opioid component (APAP, ibuprofen) Examples: Hydrocodone/acetaminophen Hydrocodone/ibuprofen Oxycodone/acetaminophen Oxycodone/aspirin Codeine/acetaminophen Tramadol/acetaminophen excelleRx, Inc. All Rights Reserved. 2012

58 Opioid Selection: Poor Choices for Chronic Pain
Meperidine Poor absorption and toxic metabolites Propoxyphene Poor efficacy, low potency and toxic metabolites Mixed agonist-antagonist Compete with agonists -> possible withdrawal Analgesic ceiling effect excelleRx, Inc. All Rights Reserved. 2012

59 Persistent/Chronic Pain
Approach to Opioid Dosing Opioid Naïve: Start low, go slow! Opioid Tolerant Stable and Tolerating: Stay on current regimen Intermittent Pain: PRN Doses Persistent/Chronic Pain 1. PRN doses x 48 hrs 2. Determine ATC needs and give breakthrough q3-4 h: 10-20% of TOTAL long acting requirement Stable and Not Tolerating: Consider opioid rotation Unstable and Tolerating: Keep current opioid, but by % depending on pain severity Unstable and Not Tolerating: Consider opioid rotation excelleRx, Inc. All Rights Reserved. 2012 59

60 Titrate only when there is inadequate pain relief without side effects
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61 When Do We Consider Opioid Rotation?
Unmanageable or intolerable adverse effects Lack of acceptable analgesia/therapeutic effect Change in patient status Patient difficulty in adhering to regimen Difficulty swallowing Transition from inpatient to home care An opioid rotation may be warranted when the patient is experiencing severe, intolerable side effects or not responding to their current opioid therapy and it simply means switching from one opioid to another. It is suggested to consult with a pharmacist to discuss proper drug and dose selection. The selection is based on patient specific factors such as the severity of pain, patient drug allergies and intolerance, patient frailty, etc. All of these factors as well as many others will be directly related to what drug and dose is recommended for the patient excelleRx, Inc. All Rights Reserved. 2012 61

62 Goals for Opioid Rotation
Select an opioid analgesic and develop a dosing regimen that will: Effectively and safely manage the patient’s pain Minimize the risk for adverse effects excelleRx, Inc. All Rights Reserved. 2012

63 What to do after converting?
It may take 3-5 days or longer for a complete transition to occur During this time, it is essential to reassess the patient’s pain and monitor for adverse effects. Titrate the new opioid as needed Short-acting, oral immediate release, single ingredient opioids: May be increased every 2 hours Long-acting, oral sustained-release opioids: May be increased every 24 hours Does not include methadone or transdermal fentanyl excelleRx, Inc. All Rights Reserved. 2012

64 Pain in Last Days of Life
Clinical presentation Facial grimacing Body stiffening Diminished kidney function Decreased perfusion, decreased clearance and accumulation of toxins I’d like to spend the last few minutes of our time today, discussing pain in the last days of life. At this point, many patients will have lost the ability to swallow and communicate effectively so we need to be aware of how to handle pain in these complicated situations as to not deny the dying patient of adequate pain control. Generally, upon clinical presentation the patient will have a diminished consciousness, so look for facial expressions like grimacing and body stiffening. We also need to keep in mind that at this point kidney function is diminished, therefore, we can expect decreased perfusion and drug clearance thus, the risk for accumulation of toxins and drug metabolites is increased. excelleRx, Inc. All Rights Reserved. 2012

65 Pain in Last Days of Life
What do we do? Assess patient to best ability and patient tolerability Rule out other causes of distress if possible & treat other symptoms if present Agitation, constipation, urinary retention Try opioid to see if behaviors diminish Palliative sedation may be the only viable option Intolerable pain and/or suffering Refractory to various aggressive interventions Intention is mitigation of distress, not to hasten death So what do we do in these situations? First we should try to rule out other causes of distress if possible (i.e. constipation, agitation, etc.) and a trial of an opioid may need to be initiated to see if behaviors diminish. If we have exhausted all of our options, ruled out all other issues (i.e. physical, spiritual and emotional), and the patient still has intolerable pain and suffering despite aggressive treatment, palliative sedation may be the only option. And remember in that situation, our intent is the mitigation of distress, not to hasten death. excelleRx, Inc. All Rights Reserved. 2012

66 Thank you for your participation!
Any Questions? This concludes today’s presentation. At this time, I would like to thank all or you for participating in today’s program. excelleRx, Inc. All Rights Reserved. 2012

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References 1. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 4th Ed 2. Bauman T. Pain Management. In. Dipiro JT, et al. Pharmacotherapy: A Pathophysiologic Approach, 5th ed pp 3. FitzGerald GA. Coxibs and Cardiovascular Disease. NEJM 2004; 351(17): 4. FitzGerald GA. COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov 2003;2: 5. FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. NEJM 2001;345(6): 6. Jacox A, Carr DB, Payne R, et al. Management of Cancer Pain. Clinical Practice Guideline No. 9. AHCPR Publication No Rockville, MD. Agency for Health Care Policy and Research, U.S. Department of Health and Human Services, Public Health Service, March 1994. 7. Levy MH. Pharmacologic treatment of cancer pain. NEJM 1996;335(15); 8. NSAID Alternatives. Med Lett Drugs Ther 2005;47:8. 9. Payne R. Opioid Pharmacotherapy. In. Berger A, Portenoy RK, Weissman DE. Eds. Principles and Practice of Palliative Care and Supportive Oncology. Philadelphia pp 10. Solomon DH, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation2004;109: 11. Wallenstein D, Portenoy R. Nonopioid and Adjuvant Analgesics. In. Berger A, Portenoy RK, Weissman DE. Eds. Principles and Practice of Palliative Care and Supportive Oncology. Philadelphia pp 12. Walsh D. Pharmacological management of cancer pain. Semin Oncol 2000;27:45-63. 13. Wong DL et al. Wong’s Essentials of Pediatric Nursing, ed. 6, St. Louis, 2001, p Copyrighted by Mosby, Inc. 14. Drug Information Handbook. 9th ed. Lexi-Comp Inc; 2001 15. © Thomson MICROMEDEX. All rights reserved. MICROMEDEX(R) Healthcare Series Vol. 123 expires 3/2005. excelleRx, Inc. All Rights Reserved. 2012


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