Pharmacotherapy Options for Mr. Wakefield
Concomitant Treatment of Chronic Pain, Sleep, Anxiety, and Depression
- Many medications designed to treat pain also have the ability to treat mood, anxiety, and sleep, while some can exacerbate these symptoms
- While risks of opioids are well known, unpleasant side effects of many other agents can contribute to suffering and result in reduced patient adherence
Antidepressants for Chronic Pain
- Produce analgesia by increasing activity in descending modulatory pathways through the inhibition of the reuptake of serotonin and/or norepinephrine
- Analgesic effect is not dependent on antidepressant activity
- Pain relief may occur sooner and at doses lower than those used for depression
- Considered multipurpose analgesics
- Can improve mood, increase pain tolerance, and improve sleep
- Tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors (SNRIs) are most commonly used
- TCAs may not be preferred due to their adverse effect profile (e.g. sedation, cardiac risks)
- Selective serotonin reuptake inhibitors (SSRIs) lack evidence for the management of chronic pain
Comparison of Antidepressants for Chronic Pain
| TCAs | Half-life (hours) | Oral Dosing in Adults | Adverse Effects |
|---|---|---|---|
| Amitriptyline1 | 15 | PAIN: 10 to 25 mg once daily at bedtime with titration to 150 mg/day DEPRESSION: titrate dose to 150-300 mg/day |
Sedation, dizziness, xerostomia, constipation, blurred vision, orthostatic hypotension, QT prolongation |
| Desipramine1 | 17 | PAIN: 10 to 25 mg once daily at bedtime with titration to 150 mg/day DEPRESSION: titrate dose to 150-300 mg/day |
Sedation, dizziness, xerostomia, constipation, blurred vision, orthostatic hypotension, QT prolongation |
| Nortriptyline1 | 25 | PAIN: 10 to 25 mg once daily at bedtime with titration to 150 mg/day DEPRESSION: titrate dose to 150-300 mg/day |
Sedation, dizziness, xerostomia, constipation, blurred vision, orthostatic hypotension, QT prolongation |
1: Off-label use in chronic pain.
| SNRIs | Half-life (hours) | Oral Dosing in Adults | Adverse Effects |
|---|---|---|---|
| Duloxetine2 (Cymbalta®) |
12 | 30 mg once daily with titration to 60-120 mg/day | Nausea, xerostomia, headache, constipation, dizziness, hypertension |
| Milnacipran2 (Savella®) |
7 | Day 1: 12.5 mg once daily Days 2-3: 12.5 mg twice daily Days 4-7: 25 mg twice daily Days 8 and on: 50 mg twice daily Can be titrated further to maximum of 200 mg/day |
Nausea, hypertension, headache constipation, dizziness |
| Venlafaxine± (Effexor®) |
5 | Extended-release: 75 mg once daily with titration to 225 mg/day | Nausea, headache, xerostomia, insomnia, diaphoresis |
2: FDA approved for chronic pain-related indication.
Anti-Depressant Drug Interactions
| Interacting Drugs | Severity | Description |
|---|---|---|
| Monoamine oxidase inhibitors (e.g. phenelzine, linezolid) | Contraindicated | Increased risk of serotonin syndrome, neurotoxicity, and/or seizures |
| Dopamine-2 antagonists (e.g. metoclopramide) | Contraindicated | Increased risk of extrapyramidal reactions / neuroleptic malignant syndrome |
| Antiplatelets / anticoagulants/ NSAIDs | Major | Increased risk of bleeding |
| QT interval-prolonging drugs (e.g. antiarrhythmics, antipsychotics, methadone) |
Major | Increased risk of cardiotoxicity |
| Central nervous system depressants (e.g. benzodiazepines, alcohol) |
Moderate | Increased risk of sedation and/or respiratory depression |
Antidepressants for Chronic Pain: Summary of Evidence
TCAs
- Moderate evidence vs. placebo for nonspecific chronic low back pain
- Effective for multiple types of neuropathic pain
- Amitriptyline most studied but is associated with higher incidence of adverse effects in comparison to other TCAs
SNRIs
- Duloxetine: moderate evidence vs. placebo for chronic low back pain; evidence of comparative efficacy lacking
- Duloxetine and venlafaxine as effective as TCAs for neuropathic pain and are better tolerated
References
- Chou R, Deyo R, Friedly J, Skelly A, Hashimoto R, Weimer M, Fu R, Dana T, Kraegel P, Griffin J, Grusing S, Brodt E. Noninvasive Treatments for Low Back Pain [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Feb. PMD 26985522 Accessed on line 8/3/16 at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0086177/pdf/PubMedHealth_PM…;
- Finnerup NB, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73.
Additional Pharmacotherapies for Low Back Pain
| Drug | Strength of Evidence - Acute Low Back Pain | Strength of Evidence - Chronic Low Back Pain | Recommendations for Mr. Wakefield |
|---|---|---|---|
| Acetaminophen | Low vs. placebo | Insufficient vs. placebo or NSAIDs | Likely ineffective but could possibly be recommended due to low cost and minimal adverse effects |
| NSAIDs | Moderate vs. placebo or other NSAIDs | Moderate vs. placebo or other NSAIDs | Likely effective but use should be monitored closely in combination with antidepressant due to bleeding risk |
| Muscle Relaxants | Moderate vs. placebo | Insufficient vs. placebo Low vs. other muscle relaxants |
Avoid due to lack of evidence |
| Benzodiazepines | Insufficient vs. placebo Low for diazepam vs. placebo |
Insufficient vs. placebo Low for diazepam vs. cyclobenzaprine, insufficient vs. other muscle relaxants |
Avoid due to lack of evidence and risk of adverse effects including abuse |
| Topical Analgesic: Lidocaine | No evidence available | No evidence available | Avoid |
| Topical Analgesic: Capsaicin | No evidence available | No evidence available | Avoid |
References
Chou R, Deyo R, Friedly J, Skelly A, Hashimoto R, Weimer M, Fu R, Dana T, Kraegel P, Griffin J, Grusing S, Brodt E. Noninvasive Treatments for Low Back Pain [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Feb. PMD 26985522 Accessed online 8/3/16 at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0086177/pdf/PubMedHealth_PMH0086177.pdf
What About an Anticonvulsant for Mr. Wakefield?
- Mr. Wakefield primarily demonstrates musculoskeletal pain and depression, and an anticonvulsant medication could be considered in the future pending his response to antidepressants and other treatment modalities
- Medications like gabapentin, pregabalin, topiramate, carbamazepine are classified as anticonvulsants
- They produce analgesia by reducing neuronal hyperexcitability through several proposed mechanisms
- Choice of anticonvulsant is usually guided by factors such as the pain diagnosis, patient characteristics, and cost of therapy and analgesia is not often immediately achieved, requiring dose titration
- They can have adverse effects on mood and central nervous system side effects
More about anticonvulsants for pain
- Adherence to the prescribed regimen is important to maximize response to therapy.
- They cause minimal central nervous system-related adverse effects.
- Onset of analgesia is usually within 1-2 days of starting treatment.
- They have no effect on mood and can be used safely in patients with uncontrolled depression.
- Evidence for long-term efficacy and safety is robust.
Anticonvulsants for Low Back Pain: Summary of Evidence
| Drug | Strength of Evidence - Acute Low Back Pain | Strength of Evidence - Chronic Low Back Pain | Recommendations for Mr. Wakefield |
|---|---|---|---|
| Gabapentin | Insufficient for radicular or non-radicular pain vs. placebo | Insufficient for radicular or non-radicular pain vs. placebo | Not indicated at this time but likely would be used in practice despite evidence |
| Pregabalin | No evidence available | Insufficient for radicular or non-radicular pain vs. placebo | Not indicated at this time but would likely be used in practice despite evidence |
| Topiramate | No evidence available | Insufficient for radicular or non-radicular pain vs. placebo | Not indicated at this time but could be of benefit in select patients with migraines and/or obesity |
| Carbamazepine | No evidence available | No evidence available | Avoid due to lack of evidence, adverse effect profile, and risk for drug interactions |
References
- Finnerup NB, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73.
- Atkinson JH, et al. A randomized controlled trial of gabapentin for chronic low back pain with and without a radiating component. Pain. 2016 Jul;157(7):1499-507
- Chou R, et al. Noninvasive Treatments for Low Back Pain [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2016 Feb. PMD 26985522 Accessed on line 8/3/16 at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0086177/pdf/PubMedHealth_PMH0086177.pdf
Comparison of Anticonvulsants for Chronic Pain
| Generation | Drug | Half-life (hours) | Sample Oral Dosing in Adults | Adverse Effects |
|---|---|---|---|---|
| First Generation | Carbamazepine* (Tegretol®) |
15 | 100 mg twice daily; titrate as tolerated to maintenance dose of 400-800 mg/day | Dizziness, sedation, nausea, vomiting, ataxia, constipation, blood dyscrasias |
| Second Generation | Gabapentin± (Neurontin®) |
6 | Week 1: 300 mg daily at bedtime Week 2: 300 mg twice daily Week 3: 300 mg three times daily; Titrate as tolerated to 1200-3600 mg/day |
Ataxia, fatigue, sedation, peripheral edema, abuse |
| Second Generation | PregabalinŦ (Lyrica®) |
6 | Week 1: 50 mg daily at bedtime Week 2: 50 mg twice daily; Titrate as tolerated to 300-600 mg/day | Somnolence, dizziness, ataxia, weight gain, peripheral edema, abuse |
| Second Generation | Topiramate¥ (Topamax®) |
21 | Week 1: 25 mg daily at bedtime Week 2: 25 mg twice daily; Titrate as tolerated to 100-200 mg/day |
Somnolence, dizziness, weight loss, fatigue, nephrolithiasis |
*FDA-approved for trigeminal neuralgia; off-label use for other pain indications
±FDA-approved for postherpetic neuralgia; off-label use for other pain indications
ŦFDA-approved for fibromyalgia and neuropathic pain; off-label use for other pain indications
¥FDA-approved for migraine prophylaxis; off-label use for other pain indications
Anti-Convulsant Drug Interactions
| Carbamazepine | Gabapentin | Pregabalin | Topiramate | |
|---|---|---|---|---|
| Central nervous system depressants (e.g. benzodiazepines, alcohol) | X | X | X | X |
| Substrates of CYP3A4* | X | X | ||
| Inhibitors of CYP3A4* | X | |||
| Antacids containing magnesium or aluminum | X | |||
| QT-interval prolonging drugs | X |
*Additional information on drug interactions involving CYP enzymes can be found here: http://medicine.iupui.edu/clinpharm/ddis/main-table
Link on substrates and metabolism
- CNS depressants + anticonvulsants = increased risk of sedation and respiratory depression
- Substrates of CYP3A4 + carbamazepine or topiramate = decreased effectiveness of substrate
- Inhibitors of CYP3A4 + carbamazepine = increased risk of carbamazepine toxicity
- Antacids + gabapentin = decreased effectiveness of gabapentin
- QT-interval prolonging drugs + topiramate = increased risk of arrhythmia
Monitoring Therapy
Efficacy
- Multidimensional pain assessment tools can guide progress and functional improvement
- Example tools for general assessment:
- PEG Pain Rating Scale
- PROMIS measures
- Example tools specific to chronic low back pain
- Oswestry Low Back Pain Disability Questionnaire
- Roland Morris Disability Questionnaire
- Example tools for general assessment:
Safety
- Review of systems and/or physical exam to identify adverse effects
- Tests
- Baseline and periodic basic metabolic panel, liver function tests, and/or complete blood count
- Serum drug levels (e.g. carbamazepine, nortriptyline)
- Baseline and periodic electrocardiogram (e.g. TCAs)
Pharmacotherapeutic Plan for Mr. Wakefield
- Identify patient-specific goals of therapy
- Reduce pain to an acceptable level
- Improve sleep
- Increase physical activity
- Return to work
- Click here to review “S.M.A.R.T” guide for goal setting
- Develop a patient-specific, evidence-based treatment plan
- Discontinue oxycodone
- Patients with high levels of negative affect may experience less benefit from opioid therapy in the setting of chronic pain
- Increased risk of opioid-related adverse outcomes in veterans with PTSD, particularly on high-dose therapy
- Start duloxetine 30 mg once daily with weekly titration as tolerated to 60-120 mg/day
- May be better tolerated than a TCA and unlike TCAs, dose of duloxetine used for chronic pain is also effective for managing depression
- Discontinue oxycodone
- Identify monitoring parameters for his medications:
- Safety
- Duloxetine
- Adverse effects including xerostomia, nausea, sedation, constipation, hypertension, and signs and symptoms of serotonin syndrome
- Baseline and periodic liver function tests
- Duloxetine
- Efficacy
- Monitor using the PEG Pain Rating Scale (click here for link to scale)
- Assess medication adherence
- Safety
PEG scale link: https://health.gov/hcq/trainings/pathways/assets/pdfs/PEG_scale.pdf
“S.M.A.R.T.” Guide for Goal-Setting
- Specific: What do I want to accomplish exactly?
- Measurable: How will I (and others) know when the goal is accomplished?
- Attainable: How will I plan steps to get myself closer to reaching my goals?
- Realistic: What am I willing and able to accomplish?
- Timely: What is my timeframe for completing my goal?
Find more at http://topachievement.com/smart.html
Reference
- Tichelaar J, Uil den SH, Antonini NF, van Agtmael MA, de Vries TP, Richir MC. A 'SMART' way to determine treatment goals in pharmacotherapy education. Br J Clin Pharmacol. 2016 Jul;82(1):280-4.
- Edwards RR, Dolman AJ, Michna E, Katz JN, Nedeljkovic SS, Janfaza D, Isaac Z, Martel MO, Jamison RN, Wasan AD. Changes in Pain Sensitivity and Pain Modulation During Oral Opioid Treatment: The Impact of Negative Affect. Pain Med. 2016 Mar 1. pii: pnw010. [Epub ahead of print]
- Seal KH, Shi Y, Cohen G, Cohen BE, Maguen S, Krebs EE, Neylan TC. Association of mental health disorders with prescription opioids and high-risk opioid use in US veterans of Iraq and Afghanistan. JAMA. 2012 Mar 7;307(9):940-7
- Krebs EE, Lorenz KA, Bair MJ, et al. Development and Initial Validation of the PEG, a Three-item Scale Assessing Pain Intensity and Interference. Journal of General Internal Medicine. 2009;24(6):733-738. doi:10.1007/s11606-009-0981-1.
Medication Adherence Strategies
Medication adherence strategies can include:
- Ongoing communication and collaboration across providers
- Simple dosing schedules and appropriate literacy considerations
- Patient monitoring of use, effect, and side effects
- Cost considerations
- Prescription monitoring checks
- Urine toxicology and pill counts
- Assessing patient’s beliefs about medication
- Evaluating where patient obtains medication information
- Enlisting reliable family, monitoring for non-therapeutic relationships
Michele Matthews Summarizes a Pharmacologic Treatment Plan for Mr. Wakefield
Mr. Wakefield’s Treatment Plan
Mr. Wakefield’s treatment plan will include:
- Care coordination between his multidisciplinary providers
- Cognitive behavioral therapy approaches for managing pain and depression, relaxation techniques, goal setting, pacing
- Physical therapy/graded exercise approaches to help improve pain, mobility, and function
- Pharmacotherapeutic management of depression and pain and monitoring the safety and efficacy of the treatments
