Polypharmacy as a rational treatment approach for chronic pain

1. Polypharmacy as a rational treatment approach for chronic pain Rollin M. Gallagher, MD, MPH University of Pennsylvania School of Medicine Philadelphia Veterans Medical Center Email: rgallagh@mail.med.upenn.edu

2. Goals of This Presentation 1) To review mechanisms of acute pain and chronic pain diseases and conditions 2) To discuss the rational use of polypharmacy and integrated multi-modality treatment for chronic pain

3. Medication selection in pain is based upon more than just pain severity Diagnosis Mechanisms of pain(s) Efficacy Clinical trial data Comorbidities: medical and psychiatric Prior treatment responses Side-effect burden, toxicity risk, drug and disease interactions

4. Medication selection in pain is based upon more than just pain severity Ease of use Dosing simplicity Titration simplicity Patient competence and convenience Pain’s psychosocial context and the doctor-patient relationship: - stigma - cost - illness behavior - risk of treatment non-adherence - risk of medication misuse

5. Public Health ChallengeHow do we prevent injuries from causing chronic pain? Injuries >> nerve damage >> pain >>acute distress continued nociception >> spinal cord damage >> fear, distress >>> brain damage >> >> chronic pain disease

7. THE END: CPRS Pain Cycle

8. Challenges of OEF/OIF Veteran Cohort Recent evidence suggests that access to pain treatment after severe limb trauma leads to better outcomes.

10. Opioid protective effect “Patients treated with narcotic medication for pain at three months post-discharge were protected against chronic pain, despite the fact that these patients had higher pain intensity levels and were thus at higher risk.” “The results presented here appear to lend support to the theory that… ..early aggressive pain treatment may protect patients from central sensitization and chronic pain.”

11. Gabapentin in the Treatment of Postherpetic Neuralgia Rowbotham and colleagues conducted a large, multicenter, randomized, double-blind, placebo-controlled clinical trial of gabapentin for the treatment of postherpetic neuralgia in 229 patients. Patients received 8 weeks of treatment with either gabapentin, titrated to a maximum of 3,600 mg/day, or matching placebo. Patients’ global impression of change, one of the study’s outcomes, is shown on the slide for week 8 of the study or at the patient’s final study visit. The percentage of patients treated with gabapentin who reported themselves on the Subjects Global Impression of Change as improved at the end of treatment was significantly greater than that of those treated with placebo. In addition, at the final week of therapy, patients treated with gabapentin had a statistically significant reduction (determined by means of an intent-to-treat analysis) in average daily pain score from 6.3 to 4.2 points, compared with a decline from 6.5 to 6.0 points in subjects receiving placebo (P<0.001). Rowbotham M, Harden N, Stacey B, et al, for the Gabapentin Postherpetic Neuralgia Study Group. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837-1842. Rowbotham and colleagues conducted a large, multicenter, randomized, double-blind, placebo-controlled clinical trial of gabapentin for the treatment of postherpetic neuralgia in 229 patients. Patients received 8 weeks of treatment with either gabapentin, titrated to a maximum of 3,600 mg/day, or matching placebo. Patients’ global impression of change, one of the study’s outcomes, is shown on the slide for week 8 of the study or at the patient’s final study visit. The percentage of patients treated with gabapentin who reported themselves on the Subjects Global Impression of Change as improved at the end of treatment was significantly greater than that of those treated with placebo. In addition, at the final week of therapy, patients treated with gabapentin had a statistically significant reduction (determined by means of an intent-to-treat analysis) in average daily pain score from 6.3 to 4.2 points, compared with a decline from 6.5 to 6.0 points in subjects receiving placebo (P<0.001). Rowbotham M, Harden N, Stacey B, et al, for the Gabapentin Postherpetic Neuralgia Study Group. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280:1837-1842.

12. What happens above the spinal cord?

13. Pain is conditionable:Expectation of Pain Activates the Anterior Cingular Gyrus

14. Serotonin and Norepinephrine inDepression and Pain

15. DIAGNOSIS There Are Many Painful Diseases and Pain Diseases

16. Recognizing Neuropathic Pain Persistent burning sensation Paroxysmal lancinating pains Paresthesias Dysesthesias Hyperalgesias Allodynias Again, recognizing common pain. We’ve talked about all these different symptoms already. Again, recognizing common pain. We’ve talked about all these different symptoms already.

17. Pain Drawing & Neuropathy Types And these are the kinds of patterns that may give you some diagnostic clues. Myeloneuropathy, some kind of a compression neuropathy. For example, carpal tunnel syndrome is an example of that, or an ulnar compression neuropathy in the distal extremities. Monotherapy, multiple -- something like sarcoidosis, where you have several different areas that don’t seem connected anatomically, where you have a systemic disease of some sort. Plexopathy, you see this often. I see a lot of this with patients with brachial plexus injuries following an auto accident. Sometimes you’ll see it postsurgically when a patient’s arm is compressed, and it’s usually one extremity completely painful. And then the polyneuropathies, which you see in diabetic neuropathy, toxic neuropathies and some systemic diseases And these are the kinds of patterns that may give you some diagnostic clues. Myeloneuropathy, some kind of a compression neuropathy. For example, carpal tunnel syndrome is an example of that, or an ulnar compression neuropathy in the distal extremities. Monotherapy, multiple -- something like sarcoidosis, where you have several different areas that don’t seem connected anatomically, where you have a systemic disease of some sort. Plexopathy, you see this often. I see a lot of this with patients with brachial plexus injuries following an auto accident. Sometimes you’ll see it postsurgically when a patient’s arm is compressed, and it’s usually one extremity completely painful. And then the polyneuropathies, which you see in diabetic neuropathy, toxic neuropathies and some systemic diseases

18. Numerical Rating Scale: Monitoring Patient Progress Improvement can be monitored Gives clinician and patient a consistent understandable measure with intra-rater reliability that facilitates discussion regarding: changes in pain, response to treatment Reduction of 2 points represents a clinically important We find, though, that in the clinic, that the numerical rating scale is actually more functional, and this is important, because first of all, you and the patient can have a common language. Patients can’t see a visual analog scale in their minds and tell you where it is, the pain is, but they can certainly tell you where the numbers are. Now, people say, “Well, how do you know it’s a 10?” Well, patients know it’s a 10. And you have to use language to help them ground their numbers in actual experience. How many people have had a patient come in and say, “But doc, it’s a 15.” It happens a fair amount. That doesn’t mean they’re histrionic. They’re just trying to get something across to you, that it really hurts badly. And what you do is, it just takes a second to say, “Look, 10, I use Joan of Arc burning at the stake. 8 is excruciating. 6 is severe.” And then they say, “Oh, okay, Doc, it’s 6, between 6 and 7.” So it’s just a couple of seconds of interaction about teaching them what the scale really means, and you really understand that when they have a 6, they’re hurting and they can’t function. Our target’s usually to get people below 5, particularly in neuropathic pain, but sometimes down here so that they can function. And a lot of people can function in this track [?] when they get below 5 in pain. The important thing about this scale is that a reduction of 2 points has been shown in good research by John Farrar and his colleagues at Penn to actually indicate a significant clinical change. In other words, people can really change their life when they get a two-point reduction in pain. So this gives you a really nice scale that’s very simple to use, and it’s the best tool we have for measuring pain. There is validation of this scale recently in neuroimaging studies showing what levels of pain actually light up the anterior cingular gyrus and other areas. We find, though, that in the clinic, that the numerical rating scale is actually more functional, and this is important, because first of all, you and the patient can have a common language. Patients can’t see a visual analog scale in their minds and tell you where it is, the pain is, but they can certainly tell you where the numbers are. Now, people say, “Well, how do you know it’s a 10?” Well, patients know it’s a 10. And you have to use language to help them ground their numbers in actual experience. How many people have had a patient come in and say, “But doc, it’s a 15.” It happens a fair amount. That doesn’t mean they’re histrionic. They’re just trying to get something across to you, that it really hurts badly. And what you do is, it just takes a second to say, “Look, 10, I use Joan of Arc burning at the stake. 8 is excruciating. 6 is severe.” And then they say, “Oh, okay, Doc, it’s 6, between 6 and 7.” So it’s just a couple of seconds of interaction about teaching them what the scale really means, and you really understand that when they have a 6, they’re hurting and they can’t function. Our target’s usually to get people below 5, particularly in neuropathic pain, but sometimes down here so that they can function. And a lot of people can function in this track [?] when they get below 5 in pain. The important thing about this scale is that a reduction of 2 points has been shown in good research by John Farrar and his colleagues at Penn to actually indicate a significant clinical change. In other words, people can really change their life when they get a two-point reduction in pain. So this gives you a really nice scale that’s very simple to use, and it’s the best tool we have for measuring pain. There is validation of this scale recently in neuroimaging studies showing what levels of pain actually light up the anterior cingular gyrus and other areas.

19. Efficacy – Medication Trials Disease specific vs Mechanism specific

20. Effect of Medications on Pain in a Preclinical Model of Persistent Neuropathic Pain This pre-clinical study showed that duloxetine was more effective than Venlafaxine, anitriptyline and gabapentinThis pre-clinical study showed that duloxetine was more effective than Venlafaxine, anitriptyline and gabapentin

21. Efficacy in Neuropathic Pain Agents with consistent efficacy demonstrated in randomized, controlled trials for neuropathic pain Lidocaine Patch 5%* (topical analgesic) Anticonvulsants: gabapentin,* valproate, carbamazepine Pregabalin Tricyclics: nortriptyline,† desipramine,† amitriptyline SNRIs: venlafaxine,† duloxetine* Opioids: oxycodone,† tramadol† GABA B agonist: baclofen† Although there are numerous medications for the treatment of neuropathic pain, those listed on this slide have demonstrated efficacy in multiple, consistent, randomized, controlled trials. As such, these agents provide an evidence-based treatment approach for neuropathic pain and will constitute the focus of this program’s discussion on pharmacological treatment. When selecting a pharmacologic treatment regimen, consideration should also be given to safety and tolerability factors such as side-effect profile and potential for drug interactions. Controlled clinical trials and clinical experience document that the lidocaine patch, because of its nonsystemic mechanism of action, has the least potential for adverse side effects or drug interactions. Among systemic agents, gabapentin, which has no significant side effects, has demonstrated favorable safety and tolerability. Based upon these factors, as well as being FDA-approved for the treatment of post-herpetic neuralgia, the lidocaine patch and gabapentin are often selected as initial treatments for neuropathic pain.1, 2, 11-14 Nortriptyline, desipramine, tramadol, and controlled release oxycodone have also demonstrated safety and tolerability profiles which are more favorable than earlier agents such as amitriptyline, phenytoin, carbamazepine, etc. 1-10 1. Backonja M et al. JAMA. 1998;280:1831-1836. 2. Rowbotham M et al.JAMA. 1998;280:1837-1842. 3. Rice AS et al. Prostaglandins Leukot Essent Fatty Acids. 2002; 66:243-256. 4. Gorson DM. Diabetes Care. 1998; 21:2190-2191. 5. Max MB et al. N Engl J Med. 1992;326:1250-1256.  6. Watson CPN et al. Neurology. 1998;51:1166-1171.  7. Watson CP. Clin J Pain. 2000;16(suppl 2):S49-S55.  8. Watson CP et al. Neurology. 1998;50:1837-1841.  9. Harati Y et al. Neurology. 1998;50:1842-1846.  10. Sindrup SH et al. Pain. 1999;83:389-400.  11. Carter GT et al. Phys Med Rehabil Clin N Am. 200X;12:447-459.  12. Rowbotham MC et al. Pain. 1996;65:39-44.  13. Galer BS et al. Clin J Pain. 2002;18:297-301.  14. Galer BS et al. Pain. 1999;80:533-538. Although there are numerous medications for the treatment of neuropathic pain, those listed on this slide have demonstrated efficacy in multiple, consistent, randomized, controlled trials. As such, these agents provide an evidence-based treatment approach for neuropathic pain and will constitute the focus of this program’s discussion on pharmacological treatment. When selecting a pharmacologic treatment regimen, consideration should also be given to safety and tolerability factors such as side-effect profile and potential for drug interactions. Controlled clinical trials and clinical experience document that the lidocaine patch, because of its nonsystemic mechanism of action, has the least potential for adverse side effects or drug interactions. Among systemic agents, gabapentin, which has no significant side effects, has demonstrated favorable safety and tolerability. Based upon these factors, as well as being FDA-approved for the treatment of post-herpetic neuralgia, the lidocaine patch and gabapentin are often selected as initial treatments for neuropathic pain.1, 2, 11-14 Nortriptyline, desipramine, tramadol, and controlled release oxycodone have also demonstrated safety and tolerability profiles which are more favorable than earlier agents such as amitriptyline, phenytoin, carbamazepine, etc. 1-10 1. Backonja M et al. JAMA. 1998;280:1831-1836. 2. Rowbotham M et al.JAMA. 1998;280:1837-1842. 3. Rice AS et al. Prostaglandins Leukot Essent Fatty Acids. 2002; 66:243-256. 4. Gorson DM. Diabetes Care. 1998; 21:2190-2191. 5. Max MB et al. N Engl J Med. 1992;326:1250-1256.  6. Watson CPN et al. Neurology. 1998;51:1166-1171.  7. Watson CP. Clin J Pain. 2000;16(suppl 2):S49-S55.  8. Watson CP et al. Neurology. 1998;50:1837-1841.  9. Harati Y et al. Neurology. 1998;50:1842-1846.  10. Sindrup SH et al. Pain. 1999;83:389-400.  11. Carter GT et al. Phys Med Rehabil Clin N Am. 200X;12:447-459.  12. Rowbotham MC et al. Pain. 1996;65:39-44.  13. Galer BS et al. Clin J Pain. 2002;18:297-301.  14. Galer BS et al. Pain. 1999;80:533-538.

22. Tricyclic Antidepressants Multiple mechanisms (Na+ channels, 5-HT & NE reuptake blockade) RCTs in diabetic peripheral neuropathy (DPN) and postherpetic neuralgia Dosing: Initiate dose at 10 mg hs to 25 mg hs and ? as tolerated to 10 mg to 50 mg If no effect at 2 weeks, continue to ? to =150 mg if needed Documented, but limited, efficacy for fibromyalgia and chronic low back pain Tricyclic Antidepressants (TCAs) TCAs act in part by inhibiting the reuptake of norepinephrine (NE) and serotonin (5-HT) into presynaptic neurons. TCAs were classified as the standard of adjuvant therapy for neuropathic pain until the late 1990s, when clinical trial results demonstrated the efficacy of gabapentin and the FDA approved the lidocaine patch 5%. However, many controlled clinical studies have demonstrated that TCAs (amitriptyline,1,2 nortiptyline,3 desipramine,1,4 and imipramine5) can significantly reduce the pain of diabetic neuropathy and postherpetic neuralgia,6 although they are not approved by the FDA for these uses. They have documented (although limited) efficacy in the treatment of fibromyalgia and chronic low back pain.7 Some patients who receive antidepressants for neuropathic pain may experience improvement in insomnia, anxiety, and depression. Onset of analgesia with antidepressants generally occurs before the onset of the antidepressant effect. The pain-relieving effect of antidepressant agents appears to be independent of their antidepressant effect.7 Significant interindividual variability exists in the efficacy, tolerability, and correct dosage of TCAs. Treatment can be initiated with a dosage of 10 mg if there is increased concern about side effects. Because several weeks may be needed before benefits are realized, titration can be a slow and frustrating process. There are no shortcuts and physicians should set appropriate expectations with the patient.8 Anticholinergic adverse events (AEs) are common with TCAs. All TCAs report these AEs in varying frequency and severity.6 The slide lists the order of AEs, starting with desipramine (fewest AEs), nortriptyline, imipramine, doxepin, and amitriptyline (most AEs).9,10 Amitriptyline should not be prescribed to people >65 years of age. Of all the drugs that are inappropriate for the elderly, amitriptyline is one of most frequently prescribed.11 A cardiac evaluation should be considered for patients older than 45 years of age before they are given a prescription. Because the TCAs appear to be almost equally efficacious, a commonsense approach for physicians is to start with the agents with the fewest AEs, unless they want to produce a specific “side effect” such as nighttime sedation.Tricyclic Antidepressants (TCAs) TCAs act in part by inhibiting the reuptake of norepinephrine (NE) and serotonin (5-HT) into presynaptic neurons. TCAs were classified as the standard of adjuvant therapy for neuropathic pain until the late 1990s, when clinical trial results demonstrated the efficacy of gabapentin and the FDA approved the lidocaine patch 5%. However, many controlled clinical studies have demonstrated that TCAs (amitriptyline,1,2 nortiptyline,3 desipramine,1,4 and imipramine5) can significantly reduce the pain of diabetic neuropathy and postherpetic neuralgia,6 although they are not approved by the FDA for these uses. They have documented (although limited) efficacy in the treatment of fibromyalgia and chronic low back pain.7 Some patients who receive antidepressants for neuropathic pain may experience improvement in insomnia, anxiety, and depression. Onset of analgesia with antidepressants generally occurs before the onset of the antidepressant effect. The pain-relieving effect of antidepressant agents appears to be independent of their antidepressant effect.7 Significant interindividual variability exists in the efficacy, tolerability, and correct dosage of TCAs. Treatment can be initiated with a dosage of 10 mg if there is increased concern about side effects. Because several weeks may be needed before benefits are realized, titration can be a slow and frustrating process. There are no shortcuts and physicians should set appropriate expectations with the patient.8 Anticholinergic adverse events (AEs) are common with TCAs. All TCAs report these AEs in varying frequency and severity.6 The slide lists the order of AEs, starting with desipramine (fewest AEs), nortriptyline, imipramine, doxepin, and amitriptyline (most AEs).9,10 Amitriptyline should not be prescribed to people >65 years of age. Of all the drugs that are inappropriate for the elderly, amitriptyline is one of most frequently prescribed.11 A cardiac evaluation should be considered for patients older than 45 years of age before they are given a prescription. Because the TCAs appear to be almost equally efficacious, a commonsense approach for physicians is to start with the agents with the fewest AEs, unless they want to produce a specific “side effect” such as nighttime sedation.

23. Other NP agents Voltage gated Calcium channels: Gabapentin: Every 3-5 days 0 0 300 mg 300 0 300 mg 300 300 300 mg 300 300 600 mg 600 300 600 mg 600 600 600 mg Pregabalin: Every 1-2 weeks as tolerated 50 mg TID or 75 mg BID 100 mg TID or 150 mg BID

24. Other NP agents Serotonin – Norepinephrine Reuptake Inhibitors (SNRIs) for diabetic neuropathy Duloxetine 20 mg or 30 mg in AM In 1- 2 weeks, if tolerated, increase to 40 – 60 mg in AM Target dose 60 mg for 3 weeks. Maximum dose 120 mg 2) Venlafaxine (Effexor) LA (check BP) 1. 137.5 mg in AM for 5 days, then increase by 37.5 mg every 5 days until 150 mg for 3 weeks 2. Increase after 2 weeks to 225 mg . 3. Increase after 2 weeks to 300 mg

25. Efficacy Comparison, Neuropathic Pain: Number-Needed-to-Treat Analyses Head to head trials not generally conducted with efficacy such as this because the number of patients for a superiority trial would be too large to be feasible. Head to head trials not generally conducted with efficacy such as this because the number of patients for a superiority trial would be too large to be feasible.

26. Evidence for Disease Specificity in Efficacy Trials for NP Pain EFFICACY: SPECIFIC FOR DISEASE? Postherpetic neuralgia Spinal cord injury pain Painful HIV neuropathy Chemotherapy neuropathy Diabetic neuropathy Phantom tooth pain? GENERALIZED TO NEUROPATHIC MECHANISM?

27. Lidocaine Patch 5%in Postherpetic Neuralgia The initial study that led to FDA approval of the lidocaine patch 5% was conducted by Rowbotham and colleagues in 35 subjects with postherpetic neuralgia with allodynia. Subjects reported the severity of their pain on a 100-mm visual analog scale (VAS) at baseline and following the application of patches that either did (active) or did not (vehicle control) contain lidocaine. Mean pretreatment VAS scores ranged from 47.2 to 49.3 mm. As shown in the slide, the active patch provided a significantly greater reduction in VAS pain score than the vehicle patch at 4, 6, 9, and 12 hours after application (P<0.001 to P=0.038). The vehicle patch, which was superior to “observational only” at 1 and 6 hours (individual time points P=0.016 and P=0.041), had an apparently short-lived effect, which was presumably due to the mechanical barrier provided by the patch. The vehicle patch resembles the lidocaine patch 5%, but it does not contain the active ingredient and was used as a placebo in this trial. The researchers concluded that the results of the study support the use of topical local anesthetic patches as a potentially significant treatment modality for postherpetic neuralgia. Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain. 1996;65:39-44.The initial study that led to FDA approval of the lidocaine patch 5% was conducted by Rowbotham and colleagues in 35 subjects with postherpetic neuralgia with allodynia. Subjects reported the severity of their pain on a 100-mm visual analog scale (VAS) at baseline and following the application of patches that either did (active) or did not (vehicle control) contain lidocaine. Mean pretreatment VAS scores ranged from 47.2 to 49.3 mm. As shown in the slide, the active patch provided a significantly greater reduction in VAS pain score than the vehicle patch at 4, 6, 9, and 12 hours after application (P<0.001 to P=0.038). The vehicle patch, which was superior to “observational only” at 1 and 6 hours (individual time points P=0.016 and P=0.041), had an apparently short-lived effect, which was presumably due to the mechanical barrier provided by the patch. The vehicle patch resembles the lidocaine patch 5%, but it does not contain the active ingredient and was used as a placebo in this trial. The researchers concluded that the results of the study support the use of topical local anesthetic patches as a potentially significant treatment modality for postherpetic neuralgia. Rowbotham MC, Davies PS, Verkempinck C, Galer BS. Lidocaine patch: double-blind controlled study of a new treatment method for post-herpetic neuralgia. Pain. 1996;65:39-44.

28. Efficacy of Controlled-Release Oxycodone in Postherpetic Neuralgia (N=50) This study evaluated the effectiveness of controlled-release (CR) oxycodone in managing steady pain, brief (paroxysmal) pain, allodynia, and pain relief. Clinical effectiveness, disability, and patient treatment preference also were evaluated. The study’s design is considered among the best because it assessed several types of pain. The study enrolled 50 patients with postherpetic neuralgia of at least moderate intensity; 38 patients completed the trial. The patients were randomized to 10 mg of CR oxycodone or placebo every 12 hours, each for 4 weeks, using a double-blind crossover design. Pain intensity and pain relief were assessed daily, and steady and brief (paroxysmal) pain, allodynia, and pain relief were evaluated weekly. Compared with placebo, CR oxycodone produced significantly (P=0.0001) greater pain relief and reductions in steady pain, allodynia (P=0.0004), and paroxysmal spontaneous pain. CR oxycodone also achieved superior scores in global effectiveness, disability, and masked patient preference. Long-term effectiveness remains to be assessed. Watson CPN, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology. 1998;50:1837-1841.This study evaluated the effectiveness of controlled-release (CR) oxycodone in managing steady pain, brief (paroxysmal) pain, allodynia, and pain relief. Clinical effectiveness, disability, and patient treatment preference also were evaluated. The study’s design is considered among the best because it assessed several types of pain. The study enrolled 50 patients with postherpetic neuralgia of at least moderate intensity; 38 patients completed the trial. The patients were randomized to 10 mg of CR oxycodone or placebo every 12 hours, each for 4 weeks, using a double-blind crossover design. Pain intensity and pain relief were assessed daily, and steady and brief (paroxysmal) pain, allodynia, and pain relief were evaluated weekly. Compared with placebo, CR oxycodone produced significantly (P=0.0001) greater pain relief and reductions in steady pain, allodynia (P=0.0004), and paroxysmal spontaneous pain. CR oxycodone also achieved superior scores in global effectiveness, disability, and masked patient preference. Long-term effectiveness remains to be assessed. Watson CPN, Babul N. Efficacy of oxycodone in neuropathic pain: a randomized trial in postherpetic neuralgia. Neurology. 1998;50:1837-1841.

29. Analgesic Therapy in PHN: A Quantitative Systematic Review Summary based on 56 blinded RCTs:

30. Efficacy Comparison, Neuropathic Pain: Number-Needed-to-Treat Analyses Head to head trials not generally conducted with efficacy such as this because the number of patients for a superiority trial would be too large to be feasible. Head to head trials not generally conducted with efficacy such as this because the number of patients for a superiority trial would be too large to be feasible.

31. Amitriptyline in SCI pain Cardenas DD et al. Pain. 2002;96:365-373. Sample: 84 patients with SCI and chronic pain Design: Double-blind, RCT with amitriptyline vs. active placebo, benztropine Results: – No significant differences were found among the groups in pain intensity or pain-related disability. – The findings do not support the routine use of amitriptyline in the treatment of chronic pain in patients suffering from SCI

32. Nortriptyline vs Placebo in Chemotherapy-induced Painful Paresthesias Hammack JE et al. Pain. 2002;98:195-203. Sample: 51 patients with painful paresthesias from chemotherapy -induced neuropathy Design: 4-week, double-blind, RCT with cross-over after  1-week washout Dose: Target dose = 100 mg/day Outcome: – no differences in pain intensity or quality of life, slight improvement in sleep on NT – SE burden higher on NT Conclusion: NT provides modest improvement, at best, in chemotherapy- induced painful paresthesias

33. Chronic facial pain and depression Gallagher, R.M., Marbach, J., Raphael, K., Dohrenwend, B., Cloitre, M.: Is there co-morbidity between temporomandibular pain dysfunction syndrome and depression?: A pilot study. Clinical Journal of Pain, 7: 219-225, 1991 Gallagher, R.M., Marbach, J., Raphael, K., Handte, J., Dohrenwend, B.: Seasonal Variation in chronic TMPDS Pain and Mood Intensity Pain, 61[1]: 113-120, 1995. Dohrenwend, B., Marbach, J. , Raphael, K., Gallagher, R.M.: Why is depression co-morbid with chronic facial pain? A family study test of alternative hypotheses. Pain 83:183-192, 1999

34. Depression and Pain Comorbidity Recent studies of depression have underscored the importance of remission, rather than just treatment response as a treatment goal. This is changing the criteria by which the effectiveness of anti-depressant medications are judged.Recent studies of depression have underscored the importance of remission, rather than just treatment response as a treatment goal. This is changing the criteria by which the effectiveness of anti-depressant medications are judged.

35. CHOOSING MEDICATION Expect partial effects: use multiple agents with different mechanisms: – from different classes – from the same class

36. Target – keeping pain below 5 to enable quality of life Improvement can be monitored Gives clinician and patient a consistent understandable measure with intra-rater reliability that facilitates discussion regarding: changes in pain, response to treatment Reduction of 2 points is clinically meaningful We find, though, that in the clinic, that the numerical rating scale is actually more functional, and this is important, because first of all, you and the patient can have a common language. Patients can’t see a visual analog scale in their minds and tell you where it is, the pain is, but they can certainly tell you where the numbers are. Now, people say, “Well, how do you know it’s a 10?” Well, patients know it’s a 10. And you have to use language to help them ground their numbers in actual experience. How many people have had a patient come in and say, “But doc, it’s a 15.” It happens a fair amount. That doesn’t mean they’re histrionic. They’re just trying to get something across to you, that it really hurts badly. And what you do is, it just takes a second to say, “Look, 10, I use Joan of Arc burning at the stake. 8 is excruciating. 6 is severe.” And then they say, “Oh, okay, Doc, it’s 6, between 6 and 7.” So it’s just a couple of seconds of interaction about teaching them what the scale really means, and you really understand that when they have a 6, they’re hurting and they can’t function. Our target’s usually to get people below 5, particularly in neuropathic pain, but sometimes down here so that they can function. And a lot of people can function in this track [?] when they get below 5 in pain. The important thing about this scale is that a reduction of 2 points has been shown in good research by John Farrar and his colleagues at Penn to actually indicate a significant clinical change. In other words, people can really change their life when they get a two-point reduction in pain. So this gives you a really nice scale that’s very simple to use, and it’s the best tool we have for measuring pain. There is validation of this scale recently in neuroimaging studies showing what levels of pain actually light up the anterior cingular gyrus and other areas. We find, though, that in the clinic, that the numerical rating scale is actually more functional, and this is important, because first of all, you and the patient can have a common language. Patients can’t see a visual analog scale in their minds and tell you where it is, the pain is, but they can certainly tell you where the numbers are. Now, people say, “Well, how do you know it’s a 10?” Well, patients know it’s a 10. And you have to use language to help them ground their numbers in actual experience. How many people have had a patient come in and say, “But doc, it’s a 15.” It happens a fair amount. That doesn’t mean they’re histrionic. They’re just trying to get something across to you, that it really hurts badly. And what you do is, it just takes a second to say, “Look, 10, I use Joan of Arc burning at the stake. 8 is excruciating. 6 is severe.” And then they say, “Oh, okay, Doc, it’s 6, between 6 and 7.” So it’s just a couple of seconds of interaction about teaching them what the scale really means, and you really understand that when they have a 6, they’re hurting and they can’t function. Our target’s usually to get people below 5, particularly in neuropathic pain, but sometimes down here so that they can function. And a lot of people can function in this track [?] when they get below 5 in pain. The important thing about this scale is that a reduction of 2 points has been shown in good research by John Farrar and his colleagues at Penn to actually indicate a significant clinical change. In other words, people can really change their life when they get a two-point reduction in pain. So this gives you a really nice scale that’s very simple to use, and it’s the best tool we have for measuring pain. There is validation of this scale recently in neuroimaging studies showing what levels of pain actually light up the anterior cingular gyrus and other areas.

37. Algorithm for Medication Selection in Chronic Pain With and Without Comorbid Depression

38. Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother

39. Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother

40. Prioritized Problem List And Goal-oriented Management PlanOsteoarthritis, spinal stenosis in 60-year-old executive/grandmother

41. Final Thoughts A medication that is effective in one neuropathic pain disorder may not be effective in others. But it may be, so try it. Mechanisms of neuropathic pain may differ in different diseases and within diseases, accounting for variability in study results. Be aware of drug interactions in patients with several chronic conditions.

42. Final Thoughts Success in rational polypharmacy requires: Establish appropriate goals—pain relief and quality of life Know mechanism and disease-specific data related to efficacy Present recommendations with confidence based upon evidence, not just charisma Establish patient and doctor responsibilities

43. Final Thoughts Success in rational polypharmacy requires: Run sequential clinical trials of medications based on efficacy, SE burden and toxicity, comorbidities, ease of use, and patient adherence. If partial effects, maintain on minimal effective dose while pursuing additional medication trials, one at a time. Look for additive benefit of several medications, targeting different mechanisms, to obtain control of pain to improve quality of life.