Pain management and opioid safety CME grand rounds
1. December 4, 2014
Optimizing Treatment for Pain
Patients and the Opioid Safety
Initiative
V2
Shannon DeGrote, PharmD
Amina Ghalyoun, PharmD
Jaclyn Sievers, PharmD
2. Objectives
I. Distinguish different types of pain and identify
appropriate first line treatments
II. Manage side effects of opioid use
III. Identify the goals and measures of the opioid
safety initiative
IV. Interpret urine drug screens
V. Recognize recent FDA changes in opioid
scheduling
3. Epidemiology
“The total number of opioid-related deaths in
the United States (>100,000 between 1999 and
2010) far exceeds the number of US military
casualties in the Vietnam War (58,000).”
1. Baumann TJ, Strickland JM, Herndon CM. Pain Management. In: Dipiiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th
ed. New York, NY: McGraw-Hill; 2011:539-541.
2. Bohnert AS, Illgen MA, Galea S, McCarthy JF, Blow FC. Accidental Poisoning Mortality Among Patients in the Department of Veterans Affairs Health System Med Care. Apr 2011;49(4):393-396
3. Franklin, Gary M, MD. Opioids for Chronic Noncancer Pain. American Academy of Neurology. 2014;83:1277-1284.
4. Pain
“An unpleasant sensory and emotional experience
associated with actual or potential tissue damage”
Rosenquist, EWK, MD. Definition and pathogenesis of Chronic Pain. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 18, 2014.)
5. Pathophysiology
Baumann TJ, Strickland JM, Herndon CM.
Pain Management. In: DiPiro JT, Talbert RL,
Yee GC, Matzke GR, Wells BG, Posey LM,
eds. Pharmacotherapy: A Pathophysiologic
Approach. 8th ed. New York, NY: McGraw-Hill;
2011:539-541.
6. Types of Pain
Description
Somatic • Skin, bone, joint, muscle or connective tissue
• Presents with throbbing and well localized
sensation of pain
Visceral • Pain from an internal organ
• Feeling of pain from different area other than
location of organ
Neuropathic • Nerve damage
• Pain described as burning, tingling, shock like, or
shooting pain
Baumann TJ, Strickland JM, Herndon CM. Pain Management. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed.
New York, NY: McGraw-Hill; 2011:539-541.
7. Acute versus Chronic Pain
Acute Pain Chronic Pain
Duration Hours to weeks More than 3 months
Causes Surgery, trauma
Pain due to a chronic
disease or condition
Prognosis Predictable Unpredictable
Complicating Issues Uncommon
Depression, anxiety,
financial issues
Treatment Primary analgesics Multimodal
Baumann TJ, Strickland JM, Herndon CM. Pain Management. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed.
New York, NY: McGraw-Hill; 2011:539-541.
8. Common Examples of Chronic
Pain
Osteoarthritis
Neuropathic pain
Fibromyalgia
Somatic pain
9. Osteoarthritis
Damage to protective cartilage in any joint of the body, most commonly
hands, knees, hips and spine
• Acetaminophen (APAP)
• Non-steroidal anti-inflammatory drugs (NSAIDs)
First line
• Topical & intra-articular analgesics
Second line
• Opioids
Third line
1. Hochberg, Marc C., Roy D. Altman, Karine Toupin April, et al. Recommendations for the Use of Nonpharmacologic and Pharmacologic Therapies in Osteoarthritis of the
Hand, Hip, and Knee. American College of Rheumatology. 2012;64(4):465-474.
2. Kalunian KC. Initial pharmacologic therapy of osteoarthritis. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24
2014.
3. Kalunian KC. Treatment of osteoarthritis resistant to initial pharmacologic therapy. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com.
Accessed September 24 2014.
10. Neuropathic Pain
Nerve damage in any area of the body, commonly feet and hands,
described as tingling or burning pain, weakness and numbness
• Tricyclic antidepressants (TCAs): amitriptyline, nortriptyline
• Anti-epileptics (AEDs): gabapentin, pregabalin*
• Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs):
venlafaxine, duloxetine*
• Central & topical analgesics
First line
• AEDs: carbamazepine, oxcarbazepine, topiramate
• Opioids
Second line
1. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on pharmacological treatment of neuropathic pain. Eur J Neurol. 2010;17:1113-88.
2. National institutte for health and care excellence. NICE clinical guideline 173: neuropathic pain - pharmacological management. Retrieved at: http://www.nice.org.uk/guidance/cg173. Accessed
20 Nov 2014.
3. Rosenquist E. Overview of the treatment of chronic pain. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24 2014.
4. Feldman EL, McCulloch DK. Treatment of diabetic neuropathy. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24 2014.
11. Fibromyalgia
Widespread musculoskeletal pain, believed to be due to amplified pain
signals and altered brain processes, accompanied by fatigue, sleep,
memory and mood issues.
• Acetaminophen
• TCAs: amitriptyline, nortriptyline, desipramine
• SNRIs: venlafaxine, duloxetine*, milnacipran*
• Cyclobenzaprine
First line
• AEDs: gabapentin, pregabalin*
• Selective Serotonin Reuptake Inhibitors (SSRIs): fluoxetine, paroxetine
• Tramadol
Second line
• Opioids
• NSAIDs
Not recommended
1. Ablin J, Fitzcharles MA, Buskila D, et al. Treatment of fibromyalgia syndrome: recommendations of recent evidence-based interdisciplinary guidelines with special emphasis on complementary
and alternative therapies. Evid Based Complement Alternat Med. 2013; 2013:485272
2. Goldenberg DL. Initial treatment of fibromyalgia in adults. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24 2014.
3. Goldenberg DL.Treatment of fibromyalgia in adults not responsive to initial therapies. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24
2014.
12. Somatic Pain
A throbbing, stabbing like pain
• Acetaminophen
• NSAIDs
First line
• AEDs: gabapentin, carbamazepine
• TCAs: amitriptyline
Second line
• Skeletal muscle relaxants: cyclobenzaprine, benzodiazepines
• Opioids for SHORT-TERM use for flare-ups
Third line
1. Walsh, Nicolas E. MD, Peter Brooks, MBBS, J. Mieke Hazes, MD<, PhD, et al. Standards of Care for Acute and Chronic Musculoskeletal Pain: The Bone and Joint Decade
(2000-2010). Arch Phys Med Rehabil. 2008;89:1830-1845.
2. Chou R. Subacute and chronic low back pain: pharmacologic and noninterventional treatment. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014.
www.uptodate.com. Accessed September 24 2014.
3. Anderson BC, Isaac Z, Devine J. Treatment of neck pain. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24 2014.
4. Drugs for pain. The Medical Letter. 2013;11:31-42.
14. Chemical Classes of
Opioids
Phenanthrenes Phenylpiperidines Diphenylheptanes
Natural
Codeine
Morphine
Semisynthetic
Hydrocodone
Hydromorphone
Oxycodone
Oxymorphone
Synthetic
Fentanyl
Meperidine
Synthetic
Methadone
Baumann TJ, Strickland JM, Herndon CM. Pain Management. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic
Approach. 8th ed. New York, NY: McGraw-Hill; 2011:539-541.
15. True Drug Allergy vs
Intolerance
“An immune-mediated allergic reaction,
usually due to production of antibodies to
the medication, that results in hives,
wheezing, swelling of the tongue/lips/face
and/or anaphylaxis”
Pichler WJ. Drug allergy: classification and clinical features. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24 2014.
16. Adverse
Drug
Reactions
VA/DoD Clinical Practice Guidelines for Management of Opioid Therapy for Chronic Pain. Available at http://vaww.sites.Irn.va.gov/pain/opioids. Accessed 24 Sept 2014.
17. Managing Opioid Side
Effects
Side Effect Recommendations Tolerance
Constipation
• Senna 8.6mg po daily
• Docusate 100mg po once or twice daily
NO
Dry mouth
• Increase fluid intake
• Artificial saliva
Yes
Nausea/
vomiting
• Ondansetron 4mg po q8hrs prn
• Prochlorperazine 5mg po QID prn
Yes
Pruritus • Diphenhydramine 25mg po q4hrs prn Yes
Sedation
• Dose adjustment
• Opioid rotation
Yes
Respiratory
depression
• Naloxone kits
• Avoid polypharmacy (benzodiazepines)
NO
Rosenquist E. Overview of the treatment of chronic pain. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24 2014.
VA/DoD Clinical Practice Guidelines for Management of Opioid Therapy for Chronic Pain. Available at http://vaww.sites.Irn.va.gov/pain/opioids. Accessed 24 Sept 2014.
18. Identifying High-Risk Patients
Comorbid conditions
○ Sleep apnea or sleep disorder diagnosis
○ Kidney dysfunction
Concurrent medications
○ Benzodiazepines, antihistamines, sedatives or
other CNS depressants
Lifestyle choices
○ Smoking, history of alcohol or drug dependence/abuse
Extremes of age
VA/DoD Clinical Practice Guidelines for Management of Opioid Therapy for Chronic Pain. Available at http://vaww.sites.Irn.va.gov/pain/opioids. Accessed 24 Sept 2014.
19. Special Considerations
Drug metabolism: liver enzyme (CYP2D6)
polymorphisms
Codeine: Black Box Warning
○ Fast metabolizers - more side effects
○ Slow metabolizers/DDIs - less effective
Electrocardiogram changes
Methadone: Black Box Warning
○ QTc prolongation
VA/DoD Clinical Practice Guidelines for Management of Opioid Therapy for Chronic Pain. Available at http://vaww.sites.Irn.va.gov/pain/opioids. Accessed 24 Sept 2014.
20. Opioid Analgesia
Warnings
Chronic pulmonary
disease
Central sleep apnea
Obstructive sleep apnea
(OSA) not on CPAP
Risk for suicide or
unstable psychiatric
disorder
Receiving treatment for
substance use disorder
(SUD)
Contraindications
Severe respiratory
instability
Acute psychiatric
instability
Active diversion and/or
SUD not in remission or
in treatment
Paralytic ileus
True allergy
VA/DoD Clinical Practice Guidelines for Management of Opioid Therapy for Chronic Pain. Available at http://vaww.sites.Irn.va.gov/pain/opioids. Accessed 24 Sept 2014.
21. Risks with Long-Term Use
Changes in sleep architecture
Respiratory depression
Endocrine changes
Immunosuppression
Opioid-induced hyperalgesia
Rosenquist E. Overview of the treatment of chronic pain. In: Post T, ed. UpToDate. Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed
September 24 2014.
VA/DoD Clinical Practice Guidelines for Management of Opioid Therapy for Chronic Pain. Available at http://vaww.sites.Irn.va.gov/pain/opioids. Accessed 24
Sept 2014.
22. Treatment of Pain
Non-pharmacologic
Rosenquist E. Overview of the treatment of chronic pain. In: Post T, ed. UpToDate.
Waltham, Mass.: UpToDate; 2014. www.uptodate.com. Accessed September 24 2014.
Acupuncture
Chiropractic manipulation
Heat and cold
Massage
Physical therapy
23. Opioid Safety Initiative
What is it?
Action plan to improve patient safety and
quality of pain management specific to
opioid therapy
Focus on prescriber education and training
Aligned with national private and public
initiatives to reduce the number of patients
on high dose opioids, overdoses, and death
Midboe, A. “Patient Safety Center of Inquiry: Promoting Patient Safety through Improved Tools for Opioid Prescribing.” Presentation for Patient
Safety Awareness Week. March 06, 2013.
Accessed online July 15, 2014.
24. Opioid Prescribing Related
Changes
Hydrocodone/acetaminophen Schedule II
Tramadol Schedule IV
Naloxone Kits available from FHCC,
Departments of Public Health, and retail
pharmacies
25. Opioid Safety Initiative
Goals
Identify veterans at immediate, short term,
and long term risk of harms associated with
high dose opioid therapy
Develop individualized clinical action plan to
mitigate risks
Educate opioid prescribers regarding
appropriate use and benefits of urine drug
screening
Midboe, A. “Patient Safety Center of Inquiry: Promoting Patient Safety through Improved Tools for Opioid Prescribing.” Presentation
for Patient Safety Awareness Week. March 06, 2013.
Accessed online July 15, 2014
26. Opioid Safety Initiative
Measures
Urine toxicology screen in the past year
Concurrent opioid (including tramadol) and
benzodiazepine users
Greater than 400mg morphine (or equivalent)
daily
Future: patients on an opioid and with active
SUD not in treatment
Midboe, A. “Patient Safety Center of Inquiry: Promoting Patient Safety through Improved Tools for Opioid Prescribing.” Presentation
for Patient Safety Awareness Week. March 06, 2013.
Accessed online July 15, 2014
27. Patient Provider Agreement
Patient-Provider Partnership Agreement. Packard Health A Community Partnership for Care.
http://www.packardhealth.org/patient/provideragreement Published 2014. Accessed November 1, 2014.
28. Urine Drug Monitoring Methods
Enzyme-Multiplied Immunoassay
(EMIT)
Gas Chromatography-Mass
Spectrometry (GC-MS)
Initial testing Confirmatory testing
Qualitative Quantitative
Contains specific antibodies against
drugs and their metabolites
Breaks down drug molecules into
ionized fragments and identifies
substances based on mass-to-charge
ratio
Rapid, inexpensive, widely available Time consuming, expensive
↑ sensitivity, ↓ specificity ↑ sensitivity, ↑ specificity
1. Gourlay DL, et al. Conneticut: PharmaCom Group, Inc;2012.
2. Standbridge JB, et al. Am Fam Physician. 2010;81(5):635-640.
3. Moeller KE, et al. Mayo Clin Proc. 2008;83(1):66-76.
29. Labs at FHCC
Urine Drug Screen (EMIT; Urine Tox Quick
Order)
○ Opiates
○ Benzodiazepines
○ Amphetamines
○ Cocaine
○ Cannabinoids
○ Phencyclidine (PCP)
Results in 24 hours
Confirmatory Test (GC-MS)
Automatic send out to Hines VA if EMIT positive for
opioids and amphetamines
Results in 48-72 hours
31. Use and Detection
Marijuana
metabolites
Single Use
2-8 days
Chronic Use
20-30 days
Cocaine hours
BEG
2-4 days
Opioid
metabolites
Heroin
40 minutes
6-MAM
4-12 hours
Codeine/Morphine
2-3 days
Oxycodone
2-4 days
Methadone
3-6 days
Amphetamine
Amphetamine
1-2 days
Methamphetamine
3-4 days
Benzodiazepine
Short-acting
3 days
Long-acting
30 days
Barbiturate
Short-acting
1 day
Long-acting
21 days
Alcohol 7-12 hours
Ethyl glucuronide
≥ 72 hours
1. Tenore PL. Journal of Addictive Diseases. 2010;29:436-448.
2. Standbridge JB, et al. Am Fam Physician. 2010;81(5):635-640.
3. Moeller KE, et al. Mayo Clin Proc. 2008;83(1):66-76.
4. Gourlay DL, et al. Conneticut: PharmaCom Group, Inc;2012.
5. Drug Testing: A White Paper of the American Society of Addiction Medicine. 2013.
32. False Positives
Alcohol
OTC cough products
Mouth wash
Marijuana
Dronabinol
Efavirenz
PPIs
Cocaine
Topical anesthetic
BZD
Sertraline ≥ 100mg
Barbiturates
Ibuprofen
Naproxen
Opioids
Poppy seeds
Fluoroquinolones
Rifampin
Verapamil
Trazodone
Amphetamines
Highly cross reactive with
many medications
Amiodarone
SSRIs
MAOIs
TCAs
Pseudoephedrine
1. Reisfield GM, et al. Annals of Clinical & Laboratory Science. 2007;37(4):301-314.
2. Gourlay DL, et al. Conneticut: PharmaCom Group, Inc;2012.
3. Tenore PL. of Addictive Diseases. 2010;29:436-448.
4. Vincent EC, et al. J Fam Pract. 2006;55(10):893-897.
5. Moeller KE, et al. Mayo Clin Proc. 2008;83(1):66-76.
6. Brahm NC, et al. Am J Health-Sys Pharm. 2010;67(16):1344-1350.
7. Vincent EC, et al. J Fam Pract. 2006;55(10):893-897.
33. False Negatives
Opioids
Rapid CYP 2D6 metabolizers
BZDs
Clonazepam
Lorazepam
Heroin
Usually undetectable; short half life
6-MAM metabolite detected for 4-6 hours
1. Reisfield GM, et al. Annals of Clinical & Laboratory Science. 2007;37(4):301-
314.
2. Gourlay DL, et al. Conneticut: PharmaCom Group, Inc;2012
3. Tenore PL. Journal of Addictive Diseases. 2010;29:436-44.
34. Frequency of Monitoring
Interagency Guideline on Opioid Dosing for Chronic Non-cancer Pain: An educational aid to improve care
and safety with opioid therapy 2010 Update.
35. Limitations of Monitoring
Results do not indicate
Length of time exposed to a medication
Amounts of a specific drug in the patient’s system
Frequency of use
True for urine drug screens: use of multiple medications in
the same family
Positive results
Reflect use over a few days
Do not indicate overall adherence or if the patient is taking
more or less than prescribed.
Negative results
Assay not sensitive to the medication a patient is taking
Do not indicate lack of use
1. Gourlay DL, et al. Conneticut: PharmaCom Group, Inc;2012.
2. Moeller KE, et al. Mayo Clin Proc. 2008;83(1):66-76.
36. Patient Case
AD is a 56 year old male with PMH
significant for lumbar spinal stenosis,
chronic back pain with sciatica, TIIDM with
moderate peripheral neuropathy, and HTN.
Pt presents for urine drug test follow up.
He’s been managed on the pain regimen
below for the past 30 days:
Morphine 45mg sustained acting PO BID
Morphine 15mg immediate release PO TID PRN
Gabapentin 300mg PO TID
40. Patient Case
Pt states he was seen in emergency
department for back pain prior to UDS
He was given 1mg hydromorphone
(Dilaudid)
Does this explain the (+) hydrocodone?
By the end of this presentation you should be able to…
- 50 million Americans are partially or totally disabled due to pain and the annual cost of pain in US is estimated to be in the billions of dollars
25 million Americans will experience acute pain and one third of Americans will experience severe chronic pain at some point. These numbers are expected to rise, as increasingly more Americans work beyond age 60 years and survive into their 80s.
The rate of prescription opioids and death due to overdose has substantially increased in the past decade, here in the US.
- In 1999 to 2007 the rate of overdose due to opioid prescriptions rose 124%
Of the more than 300 million prescriptions written for analgesics in 2010, 128 million of those were for hydrocodone/acetaminophen making it the most prescribed drug in the US.
The total number of opioid-related deaths in the United States (>100,000 between 1999 and 2010) far exceeds the number of US military casualties in the Vietnam War (58,000).”
The definition of pain is a “Localized physical suffering associated with bodily disorder”
“A basic bodily sensation is induced by a noxious stimulus, received by naked nerve endings, is characterized by physical discomfort (as pricking, throbbing, or aching), and typically leading to evasive action.”
Pain is often subjective and may clinicians define pain as how the patient describes it. Pain in one patient can be completely different than pain in another, so always keeping in mind the specific patient’s perception of pain is the key to treatment success.
I liked to take a minute and ask the audience how patients have described pain to you?
I suspect they may say things like... sharp/shooting/feels like pins and needles (neuropathic pain!), or maybe... dull/achy (musculoskeletal pain!). Important to distinguish, AND will be a great lead in to your next slides
The pathophysiology of pain is a complex array of neural networks in the brain that is affected by afferent stimuli.
A sensation of pain starts by the stimulation of free nerve endings known as nociceptors (seen here at the bottom of the picture). As you can see these receptors are found in both somatic and visceral structures. They are activated by mechanical, thermal, and chemical impulses.
The activation of the receptor leads to transmission along the afferent nerve fibers to the spinal cord (notice the arrows pointing upwards toward the spinal cord). If the transmission is along the myelinated fibers, a sharp, well-localized pain sensation can be felt. If the transmission is along the unmyelinated fibers, a dull, aching, poorly localized pain can be felt.
These pain processes reach the brain through a complex array of ascending spinal cord pathways and it is postulated that the thalamus acts as a relay station for these sensations. These signals then ascend and pass through to central structures where pain can be further processed. The brain is thought to only accommodate a limited number of pain signals that can be modified both cognitively and behaviorally.
Practices such as relaxation, distraction and meditation may decrease pain by limiting the number of processed pain signals. Certain diseases states, such as anxiety or depression, are thought to worsen pain as the neurobiochemical makeup of the brain is different.
Various neurotransmitters and receptors are responsible for the transmission of pain impulses. The CNS also has a highly organized descending system for pain transmission. Lastly, inflammatory pain is thought to be the body’s own defense from preventing tissue damage to the promotion of healing. Due to the inflammatory process, the pain threshold is reduced and the injured area is more sensitive to pain. When this process outlives its functionality in diseases such as arthritis, it can move from an acute pain to more chronic pain.
Neuropathic pain is different from nociceptive pain in that is has nothing to do with the noxious stimuli or healing and is a result of nerve damage. Functional pain is thought to be abnormal operation of the nervous system. Neuropathic pain is commonly known as postherpetic neuralgia or diabetic neuropathy, where as functional pain is more fibromyalgia, irritable bowel syndrome, or tension-type headaches. This type of pain is often not evident by examining physical findings.
There are three types of pain, somatic, visceral and neuropathic. Somatic pain is pain from the skin, bone, joint, muscle or connective tissue and usually presents with throbbing and well localized sensation of pain. Visceral pain is from an internal organ and presents with the feeling of pain from different areas other than the location of the organ. An example of this is during a heart attack, a patient may complain of numbness in his left arm. The last type of pain is neuropathic pain and this is pain from the nerve. The usual presentation is described as continuous pain and feels like burining, tingling, shocklike or shooting pain.
Acute Pain is nociceptive in nature and is a physiologic process that can warn individuals of disease states or potentially harmful situations. Acute pain subsides quickly as healing processes decreases pain-producing stimuli, so the duration is usually hours to weeks. Some common causes are surgery or trauma and the primary treatment is analgesics. Chronic Pain is pain that persists for months to years and it can be nociceptive, neuropathic/functional or mixed. Causes may be due to pain from a chronic disease or condition and some complicating issues may be related to depression or anxiety like I previously mentioned. Treatment for chronic pain is multimodal, which we will discuss shortly. However, it is important to know that chronic pain is often more difficult to treat.
And again, pain is often subjective, so keeping in mind how the patient describes it and there perception of pain will help guide practitioners in choosing the right therapy.
So moving into the pharmacologic treatments of pain, the treatment choice can depend not only on the severity of pain but also the type of pain.
We will be focusing on four common types of pain: back and neck pain, osteoarthritis, neuropathic pain (diabetic, postherpetic and others) as well as fibromyalgia.
Damage to the protective cartilage in any joint of the bone, most commonly hands, knees, hips and spine
Acetaminophen is 1st line for non-inflammatory OA
Acetaminophen has more to do with the inhibition of central prostaglandin synthesis than inflammation
OA commonly presents with inflammation of the joints and this is when NSAIDS should definitely be used
NSAIDs work to reduce pain and inflammation by inhibiting enzymes, called cyclooxygenases.
By inhibiting cyclooxygenases, NSAIDs help to prevent and/or reduce pain and inflammation
There are two main types of NSAIDs, nonselective and selective
Nonselective NSAIDs inhibit both COX-1 and COX-2 enzymes to a significant degree.
Selective NSAIDs inhibit COX-2, an enzyme found at sites of inflammation, more than the type that is normally found in the stomach, blood platelets, and blood vessels (COX-1).
Examples of nonselective NSAIDS include drugs commonly available without prescription, such as aspirin, ibuprofen and naproxen (Aleve), as well as many prescription strength NSAIDS
Selective NSAIDS are as effective in relieving pain and inflammation as nonselective NSAIDS and are less likely to cause GI injury. Example of this is celecoxib (Celebrex)
Patients taking one NSAID should not take a second NSAID at the same time.
If low doses of NSAIDs are not fully effective, practitioners may recommend using a higher dose of the NSAID on a regular basis for several weeks to improve the antiinflammatory benefits of these drugs.
Topical capsaicin is an alternative to oral NSAIDS or APAP for those who cannot tolerate them or who are at increased risk of ADRS (especially >75 yo and cardiac risk of NSAIDS)
Unfortunately, capsaicin is plagued with a slow onset of therapeutic benefit
Making sure to prescribe capsaicin as a scheduled dose, rather than as needed is important to achieve the full therapeutic benefit
Intraarticular glucocorticoids are another potential option, esp if the pain is in one or only a couple of joints
We limit the use of opioid analgesics to pts with moderate to severe pain in whom who interventions have failed
It may be beneficial short term for treatment of exacerbations but remember OA is primary inflammation of joints and opioids do not have any anti-inflammatory effects
If opioids are used, they should be in combination with an NSAID
Nerve damage in any area of the body, commonly feet and hands, described as tingling or burning pain, weakness and numbness
The first line of treatment is tricyclic antidepressants and Amitriptyline has the most evidence.
Amitriptyline is however not well tolerated. Even at lower doses than those used to treat depression (25 to 50 mg) dry mouth, constipation, fluid retention, weight gain, grogginess, and difficulty concentrating are common. Such side effects and possible cardiotoxicity limit use in older patients.
Nortriptyline is a tricyclic antidepressant that has been less well-studied for neuropathy but this drug is a possible alternative because it generally has fewer anticholinergic side effects and can potentially be used in the patient population >65 years as it has recently been taking off the BEERS criteria.
Anti-epileptic drugs, both newer and older may be useful. However, specifically those that are alpha-2 ligands such as gabapentin and pregabalin have been shown to be effective.
Clinical trials in diabetic neuropathy and postherpetic neuralgia have shown that gabapentin at 2400-3600 mg/day have efficacy similar to TCAs.
Of note, pregabalin is non-formulary and gabapentin must be tried first
For SNRIS, venlafaxine is commonly used first and higher doses such as 150 to 225 mg daily are associated with significantly more benefit
Pain relief with venlafaxine is associated more with norepinephrine than serotonin and thus higher doses of venlafaxine should be used to achieve norepinephrine re-uptake inhibition
Duloxetine is effective as well.
Central and topical analgesics are approved for postherpetic neuralgia and can be used when the pain is more localized
Carbamazepine and oxcarbazepine are more second line agents for neuropathic pain, however they are used first line in specific types of neuropathic pain such as trigeminal neuralgia
Opioids have been showed to be moderately beneficial. However most of the clinical trials are limited by short term follow up and thus they are used more of a last line treatment
Widespread musculoskeletal pain, believed to be due to the amplified pain signals and altered brain processes, accompanied by fatigue, sleep memory and mood issues
First line medications include APAP
NSAIDS may also be tried but are less likely to be effective as there is no evidence that tissue inflammation is present in fibro.
Like neuropathic pain, TCAs work in fibromyalgia and amitriptyline has the most evidence.
SNRIs are useful if the pt suffers from more fatigue and depression
Milnacipran is a new SNRI that was only FDA approved for treatment of fibro. This medication has some benefit in treating pts with severe fatigue, however it has not consistently shown to be more effective than venlafaxine or duloxetine
Cyclobenzaprine has a similar structure and similar effects and is used to treat muscle spasms
Second line agents include anti-epileptic drugs , especially the alpha 2 ligands and these are beneficial in those pts intolerant to TCAS or have more problems with insomnia
SSRIS, such as fluoxetine and paroxetine and have shown more benefit in those with fibromyalgia and depression
Tramadol may be used for short term relief of exacerbations and that is due to more of its SNRI activity then it’s opiate activity
Opioids are not recommended as a number of reports suggest they are associated with negative outcomes
Because FM symptoms tend to persist over time and only rarely are completely resolved, the risk of opioid use outweighs the benefits with the concern for misuse and abuse, as well as the long term side effects of opioid use, which Shannon will discuss in a later section
Type of somatic pain that is characterized by throbbing or stabbing like pain
APAP and NSAIDS have been shown to be equally effective
This includes both OTC and prescription
Second line agents include anti-epileptic drugs and antidep similar to those seen with neuropathic pain.
These tend to be more effective in those with sciatic-like nerve pain related to back pain or w/ injuries to the spinal cord
Third line agents include skeletal muscle relaxants and opioids which have shown evidence in short term exacerbations and muscle spasms
Opioids may be beneficial 1 hour before anticipated incident pain, such as physical therapy, however you want to make sure the pt doesn’t associate benefit with the medication and not therapy
Important to treat exacerbations so pt can continue with activities as this leads to quicker recovery compared to a pt that is bed bound due to pain
So moving onto talking about opioids specifically, the highlight of our talk today, here are some interesting facts:
Humans have used opium for its mind altering effects longer than any drug (with the exception of alcohol) with uses that date back to 4000 B.C (and possibly earlier – predating any documented records).
It wasn’t until 1805 that a German chemist isolated the active ingredient in opium, and named this chemical morphine, after Morpheus, the Greek god of dreams.
There are three main classes of opioids, phenathrenes, phenylpeperidines and diphenylheptanes. Not included in this slide is tramadol as it has not classically been defined as an opiate although it does have actions the opiate receptors.
This is an important slide to remember as if a patient has a true allergy to one of the above medications, they can be switched to a different drug in a different class and would not be expected to have the same reaction.
So for example, if a patient has a true anaphylaxis reaction to morphine (not just a rash but hives and/or swelling in the throat), fentanyl can be used
Non-Formulary: Oxycodone CR, oxymorphone, fentanyl and meperidine. Methadone requires having a pain specialist who has experience in dosing this medication
So what is a true drug allergy vs an intolerance or side effect?
The key here is that a true allergy is immune mediated and typically involves production of antibodies that leads to hives, wheezing, swelling of the tongue/lips/face and/or anaphylaxis.
Additionally, most allergic reactions are not dependent on the dose. Where as side effects become more pronounced at higher or toxic doses.
Side effects can be treated and most will resolve without a change in medication.
So then what are the side effects of opioids?
Here’s a graphic to help visualize all the various side effects associated.
I will be going into more depth on some of the more common side effects on the next slide, but as you can see here there are several CNS effects including drowsiness, fuzzy thinking, anxiety and N/V.
Narrowing of the pupils or miosis is seen along with dry mouth and throat, breathing can be more difficult and slowed or irreguar, along with several effects to the gastric, intestinal and urinary systems.
To go into more depth on some of the side effects and how to manage them, we will start with constipation, one of the more frequent complaints and one out of two side effects in which tolerance is not gained.
It is caused by Mu receptor activation in the bowel that leads to decreased colonic mucosal secretion, increased rectal sphincter tone, and decreased peristalsis.
Thus it is very important to have a stimulant laxative like senna on board due to this slowed gut motility.
Dry mouth is caused by some of the anticholinergic side effects associated with side effects.
And not only is increased fluid intake, so 6-8 glasses of water, important to help treat dry mouth but also constipation.
As well as artificial saliva can help with the dry mouth.
The most common complaint of opioid therapy is nausea and vomiting which is mediated by stimulation of the vestibular system, the chemo receptor in the medulla, and the peripheral stimulation in gut as we just discussed.
There are several medications to help treat this but ondansetron is the most common as the others are associated with more side effects.
It is important to note that while 2/3rds of patients will complain of this at the start of therapy, tolerance will develop.
Pruritus is most commonly associated with morphine, but technically any opioid can cause a displacement of histamine in the cells.
Thus opioids cause a release of histamine into the extravascular and intravascular space leading many patients to experience pruritus and hypotension.
Hence antihistamines are best suited to treat this, but do note that tolerance will develop to this side effect as well.
Sedation is often a precursor to respiratory depression, however tolerance will develop unlike respiratory depression.
But it is a very important side effect to pay attention to especially when increasing the dose or switching opiates.
It can be a serious situation that can require holding 1-2 doses of opioids, then reducing the dose by 25% and/or increase frequency of administration (so from q6 to q8).
Additionally, you could consider opioid rotation as certain patients may be less likely to experience sedation with certain opiates than others.
So then respiratory depression is caused by a depression of central respirations in the brain stem.
Tolerance does not develop hence why it is important to always be mindful of this side effect and to treat it with the naloxone kits which we will go into more depth later.
It is also important to watch for polypharmacy, especially with benzodiazepines as they cause a relaxation of the diaphragm muscle while the opiates work centrally to depress respirations.
Thus you have two different mechanisms of action that act synergistically to increase the risk of respiratory depression. Who who else is at risk for respiratory depression, overdose or abuse of opiates?
So some other patients who are also high risk are those with certain comorbid conditions like sleep apnea, sleep disorder diagnosis or those with kidney dysfunction.
Or those with certain comorbid medications like benzos as discussed, antihistamines, sedatives or other CNS depressants.
Those with certain lifestyle choices like smoking, current or history of alcohol or drug dependence/abuse.
Additionally, extremes of age which not only includes the elderly older than 65 and infants but also interestingly children.
So why are children at more risk of overdose and respiratory depression?
Children are at more at risk due to drug metabolism. Liver enzyme function peaks around age 11-13 thus they are metabolizing drugs much more efficiently than any other age group.
Additionally, if they have this genetic polymorphism of the cytochrome 2D6 liver enzyme that causes them to be fast metabolizers they will experience a lot more side effects.
These metabolism pathways will be discussed further in later slides but essentally fast metabolizers will be metabolizing codeine into morphine, hydrocodone into hydromorphone and oxycodone into oxymorphone much more rapidly than those with normal or slow metabolism.
So if you have an 11-13 year old with peak liver function and an ultra rapid metabolizer they will convert codeine into morphine more rapidly and completely than others, resulting in higher than expected serum morphine levels and possible overdose symptoms.
However, this is only a black box warning for codeine as it is commonly prescribed for children after tonsillectomies as demonstrated in this graphic that shows 500-800,000 rx/year being prescribed to children.
The prevalence of 2D6 fast metabolizers is estimated at 16 to 28% in North Africans, Ethiopians, and Arabs, 1 to 10% in Caucasians, 3% in African Americans, and 0.5 to 1% in Hispanics, Chinese and Japanese.
Chinese and Japanese people tend to have the slow metabolizer polymorphism and thus this medication may provide less pain relief.
Another special consideration amongst opioids, is methadone for its potential to cause changes in the ECG, specifically the QTc interval.
It is a black box warning to avoid using methadone in any one with a QTc >500ms and to exert caution in anyone who is on other medications that also have the potential to prolong the QTc interval.
Due to the risks associated with opioids, there are several contraindications and warnings regarding respiratory problems and psychiatric issues.
Contraindications include, severe respiratory instability, acute psychatric instability, active diversion or substance use disorder not in remission or in treatment with opioids or any drug of abuse, paralytic ileus and true allergy as we have previously discussed.
Warnings include chronic pulmonary disease like central sleep apnea and obstructive sleep apnea if they are not using a CPAP, risk or unstable psychiatric disorder or receiving treatment for substance use disorder.
Moving onto risks with long term use, not only are those with sleep disorder diagnoses are at more risk but there is also some evidence that opioid use causes changes in sleep architecture.
Some studies show that there is a higher percentage of sleep disorders in patients with opiates, for example one study showed 30% of methadone users had central sleep apnea, 36% had OSA and 21% had mixed disorder.
These changes in sleep architecture also put patients at more risk for respiratory depression.
Which as previously mentioned, will always be a risk for anyone on chronic opioid therapy as tolerance does not develop.
There is also a wide array of endocrine changes with chronic opioid use.
Hormone levels tend to be much lower in chronic opioid users and testosterone even showed an apparent dose-response effect.
One study showed that 87% of men with normal erectile function before use will report issues with ED or libido after beginning opiate treatment.
Estrogen, FSH and LH have also been shown to decline, which can cause altered menstrual flow and infertility.
A decrease in bone mineral density is also a long-term side effect that is not only due to the hypogonadism but other mechanisms as well.
A recent systematic review found a relative risk of 1.38 for fracture of any type for patients on chronic opioid therapy.
Not only is there endocrine changes, but also several changes in the immune system.
However, the immunosuppression occurs both with acute and chronic use.
The immunosuppression is medicated by an inhibition of lymphocyte proliferation, hematopoietic cell development and acceleration of apoptosis.
Lastly, opioid-induced hyperalgesia is a risk with long term use.
This is where a patient experiences increased pain or sensitivity without a change in their underlying medical condition.
However, unlike what you would expect with opioid induced tolerance or an actual worsening of their underlying medical condition, the patient would actually be unable to obtain adequate pain relief despite increasing opioid doses.
You would actually be expected to see a paradoxical reduction in pain with reduced doses of opiates.
This is an important risk to keep in mind as patients begin to require higher and higher doses without a change in their condition or without much additional pain relief benefit.
So then to conclude the treatment of pain with the non-pharmacological options.
These include acupuncture, chiropractic manipulation, heat and cold, massage and physical therapy.
There are even more non-pharmacologic options than listed in this slide, such as yoga, pilates, biofeedback and other psychological treatments.
As previously mentioned, chronic pain is typically more difficult to treat and requires a multimodal approach to treatment thus they should be trying at least one non pharmacological treatment with or without medications.
It is not necessary or always appropriate for every patient to try each of these non-pharmacological options, but it is important to know and share all the potential options out there as what one treatment works for one patient may not work for the next.
Not only due to perceived efficacy but also due to financial and time requirements.
Now to hand it over to my co-resident who will be speaking to you about the opioid safety initiative.
23 states are providing naloxone kits for free via community agencies
New labeling for extended release/long acting opioid products
“Indicated for the management of pain severe enough to require daily, around-the-clock, long term opioid treatment and for which alternative treatment options are inadequate”
FDA
Patient-Prescriber Agreement
Drug research expectations
SO, how will the schedule changes affect their prescribing? FEDERAL restrictions on CII and CIV are:
At our facility EMIT takes about 24 hours to return. It is a general tox screen, checks for 6 drugs, and detects +/-. If it comes back positive for opiates, amphetamines, or cannabinoids it will automatically be sent to Hines for confirmatory testing GC-MS. The return from Hines takes an average of 48 hours, sometimes 72 hours. We have one instrument and it is old so delays can happen. There is a test that providers can order through QUEST which is used to monitor opioid therapy (like in primary or specialty care settings). This test is expensive (im not sure how much it costs). This test is much much more specific and is sent to Chantilly, Virginia. It can take about 7 days to return. It is more detailed/quantitative.
Talking points: EMIT is performed first, explain how it works and what it detects (natural opiates i.e. morphine and codeine, maybe a few of the semi-syntehtic). When you order confirmation testing it goes to Hines and is run via GC-MS, this is more specific and can detect things such as.... xyz.
Opioid screening tests typically detect morphine, a common metabolite of not only heroin but all natural (eg, codeine) and older semisynthetic (eg, hydromorphone) opioids. Synthetic opioids, including fentanyl, meperidine, methadone, pentazocine, propoxyphene, and tramadol, are not detected by routine opioid screening. The semisynthetic opioids oxycodone and oxymorphone, which are widely prescribed and abused, are also not detected by routine opioid screening. However, a specific oxycodone screening assay that detects both oxycodone and oxymorphone is available and commonly used to detect these drugs. Buprenorphine is a semisynthetic opioid agonist-antagonist used in substance abuse programs whose detection requires a specific assay.
I would add what this tests for. Morphine (if positive it automatically tests for 6-MAM (use the real name) which is 100% indicator of heroin use), codeine, hydrocodone, oxycodone, hydromorphone (for a total of 5 drugs).
If you are asked.... tramadol can NOT be detected in these tests
on the confirmation bullet, explain where it goes, how long it takes, etc
Important slide to explain metabolites. Walk through an example. If a patient is being prescribed morphine and hydrocodone is detected on confirmation testing, what does that mean? Can hydrocodone be a metabolite of morphine... no!
Talk about rapid metabolizers or even patients with little to no CYP 2D6 Activity.
The evidence suggests that, unlike most other CYP450 enzymes, CYP2D6 is not very susceptible to enzyme induction. Thus, genetics, rather than drug therapy, accounts for most ultrarapid CYP2D6 metabolizers.
Codeine is largely a prodrug, and its activity is primarily dependent on its conversion to morphine. Patients who have little CYP2D6 activity, therefore, are likely to have little response to codeine. The number of people with low CYP2D6 activity is substantial, when one considers the people genetically deficient in CYP2D6, plus the many patients who are taking CYP2D6 inhibitors. A more dangerous situation, however, occurs when ultrarapid metabolizers take codeine. They may develop moderate-to-severe adverse effects from excessive morphine concentrations in the blood
There’s a cool table at the source of this info in regards to diffs in ethnicity and CYP2D6
http://www.pharmacytimes.com/publications/issue/2008/2008-07/2008-07-8624
Summary of when and how substances are ingested versus and how this affects their detection in the urine
Opioids
Naturaldetectable
Morphine
Codeine
Syntheticsundetectable
Fentanyl
Methadone
Tramadol
Basically purpose of this slide to show that depending on drug formulation, it’s pharmacokinetics, and way pts use it will affect the results of the assay.
Strategies to improve analysis and interpretation of results
Also, include some of the clinical pharm emails about interp of results for some tests
Verapamil with methadone only
Trazodone with fentanyl only
What is the false neg mech behind BZD?
RESULTS:
Point of care assays yielded false negative results for patients prescribed benzodiazepines nearly 20% of the time (98 out of 498 patients). The point of care cup often failed to produce positive results for persons who were shown by LC-MS/MS to be taking lorazepam or clonazepam. Although only 26 out of 498 patients (5%) were prescribed ≥2 benzodiazepines, 73 out of 498 patients (15%) were found to be positive for that drug class.
http://www.ncbi.nlm.nih.gov/pubmed/22484396
Lacey miller ppt
Recommended by COT
Re-iterate false pos
Ask me if you have questions. This slide may provoke a lot of questions... providers are ALWAYS asking me about how to interpert UDS.
Discuss pharmacogenetics that come into play? Such as rapid metabolizers or
Need to know the NF process for naloxone in case anyone asks
Important slide to explain metabolites. Walk through an example. If a patient is being prescribed morphine and hydrocodone is detected on confirmation testing, what does that mean? Can hydrocodone be a metabolite of morphine... no!
Talk about rapid metabolizers or even patients with little to no CYP 2D6 Activity.
The evidence suggests that, unlike most other CYP450 enzymes, CYP2D6 is not very susceptible to enzyme induction. Thus, genetics, rather than drug therapy, accounts for most ultrarapid CYP2D6 metabolizers.
Codeine is largely a prodrug, and its activity is primarily dependent on its conversion to morphine. Patients who have little CYP2D6 activity, therefore, are likely to have little response to codeine. The number of people with low CYP2D6 activity is substantial, when one considers the people genetically deficient in CYP2D6, plus the many patients who are taking CYP2D6 inhibitors. A more dangerous situation, however, occurs when ultrarapid metabolizers take codeine. They may develop moderate-to-severe adverse effects from excessive morphine concentrations in the blood
There’s a cool table at the source of this info in regards to diffs in ethnicity and CYP2D6
