American Journal of Therapeutics 10, 318-323 (2003) Efficacy of Venlafaxine for the Long Term Treatment of Chronic Pain With Associated Major Depressive Disorder Ronald H. Bradley,'* Robert L. Barkin,’” John Jerome,! Kevin DeYoung, and Charles William Dodge’ Background: This was an open-label, single-center study of the long-term efficacy and effectiveness of venlafaxine extended release (XR) in the treatment of chronic pain and depression in outpatients Al patients have been diagnosed with major depressive disorder (MDD) of various types, with or without chronic pain, and had previously failed treatment with either trleyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs). Methods fficacy of treatment was determined using the 21-item Hamilton Rating Scale for De- pression (HAMD-21), the Visual Analogue Scale (VAS) for the evaluation of pain, and a 12-tem quality of life scale (QOL), Patients were treated in an unblended open trial for 1 year with 150 mg or more of venlafaxine XR once daily. Results: After 1 year of treatment, 21-item Hamilton Rating Scale for Depression, Visual Analogue ‘Scale, anc quality of life scores were significantly improved from permanent baseline scores. ‘Conclusion: These data show long-term elficacy and effectiveness of venlafaxine XR, a serotonin (G-HT) and norepinephrine (NE) and dopamine (DA) reuptake inhibitor antidepressant agent, having analgesic properties. ‘Keywords: depression, venlafaxine, analgesia, antidepressant, pain INTRODUCTION Chronic pain may be associated with psychiatric dis- orders such as depression. The management chal- lenges of chronic plain focusing upon the role of an- tidepressants have been reviewed. The association be- tween pain and depression is complex—each may occur independently as a primary condition, although pain and depression may develop secondarily to each other or may jointly coexist“ Patients with chronic “Total Healt Care of Michigan, P.C, Bust Lansing, Ml; and *Assoiate Profesor, Rush Medical College, Faculty: Anesthesiol ogy, Family Medicine, Pharmacology, Psychiatry, Rusk Prstyte- rit St, Lukes Medical Center Chicago tL; The Rush Pain Center, Chicago, IL; and The Rush North Shore Pain Center, Ski, I “Address for correspondence: Tota HealthCare of Micon, P-C 2900 Hannah Biod. Ste. 200, Eat Lansing, MI 48823, USA ail: ribradley@misn.com 1075-2765 © 2003 Lippincott Williams & Wi pain are at risk for developing depression.‘ The patho- physiologic pain classification is provided on Table 1. Untreated pain? and untreated depression can se- verely affect quality of life (QOL).' Because sero- tonergic (-HT) and noradrenergic (NE) neurotrans- ‘mission is involved in the elaborate pathways medi ating analgesia, antidepressant agents that jointly modulate both of these neurotransmitter (ie, have a ‘ual mechanism of action) have been used extensively and more effectively in the treatment of pain, includ: ing chronic pain.1°>* Such dual mechanism agents are also considered the most effective treatment of depression.'°"” Venlafaxine extended release (XR) is a newer gen- eration, serotonin reuptake inhibitor (SNRI, antide- pressant that is additionally indicated for generalized anxiety disorder (GAD). In a dose dependent manner, venlafaxine inhibits reuptake of both serotonin and norepinephrine, and to a lesser extent dopamine; it is thus classified as a serotonin and norepinephrine re- uptake inhibitor. Because of its selective action at theVenlafaxine for Chronic Pain With Major Depression 319 Table 1. Pathophysiologic pain classification Organic etiology Neuropathic (deafferentation) From primary lesion or dysfunction within the nervous system Pain signals arrive contrally and are disproportionate to initial stimulus (central sensitization} Nonnociceptive: peripherally, centrally, or sympethically mediated May be associated with involvement of peripheral nerves Pain periodicity is intermittent or continuous Patient presentation: allodynia, hyperpethia, hyperalgesia, and pseudomotor abnormalities May benefit from treatment with antidepressants (Le., dual mechanism: mirtazapine, venlafaxinel, ‘anticonvulsants (ie, topiramate) sodium channel blockers, centrally acting analgesics (tramadol), excitatory ‘amino acids modulators, or calcium channel, NMDA receptor antagonist blockers Nociceptive jacute: somatic, visceral) ‘Somatic: wall localized from peripheral tissue injury/trauma without nervous system damage, inflammation, hyperalgesia (.e., mechanical, thermal, chemical, ischemic stimuli; results from release of inflammatory cascade Peripheral activationistimulation, excitation, end sensitization of nociceptors at somatic and viscoral sites (vessels, skeleton, joints, neurons, muscles) Benefits fram some opioids and nonsteroidal antiinflammatory agents (ie., rofecoxib), centrally acting agents {teamadol), glucocorticosteroids, skeletal muscle relaxants, bisphosphonates (ie, alendronate} Viscoral: (poorly localized} viscarai afferent transmission by sympathetic nerves entering the dosal horn of spinal cord with corresponding spinal dorsal root nerve Benefits: from some opioids, centrally acting agents (tramadol) Mixed or undetermined, unspecified, unknown Chronic cephalalgia Vascular pain Benefits from multidisciplinary approach of cognitive or behavioral therapy, physical therapy, pharmacotherapy Paychagenic etiology Psychologie/esychiatric conditions with significant features of pain after complete exclusion of somatic pathologie findings (e.g., somat ion, pseudohypochrondriasis); benefits from psychotherapy, cognitive behavioral therapies, physical therapies, pharmacotherapy, nonpharmacotherapies dual reuptake sites (NE/5-HT) in the central nervous system and its lack of TCA postsynaptic action on muscarinic (M) and alpha (a) adrenergic or histamin- exgic (H,, H,) receptors, it has a more favorable side effect profile compared with tricyclic antidepressants (TCAs). Previous studies have shown the short- and long-term efficacy, tolerability, and safety of venlafaxine as an antidepressant."""™!° The pharma- cokinetics of venlafaxine are described in Table 2. An analgesic effect of venlafaxine has also been re- ported.'"7 In one (1) case study of a patient with both depression and chronie pain, venlafaxine was ef- fective as both an analgesic and an antidepressant.** Recent studies have described the effectiveness of ven~ lafaxine in alleviating pain associated with diabetic neuropathy." In our study, the long-term efficacy of venlafaxine XR as an analgesic and antidepressant agent was examined in outpatients diagnosed with depression or depression-comorbid chronic pain Chronic pain syndromes frequently encountered in primary care that are antidepressant responsive are presented in Table 3. METHODS ‘This 1-year, open-label unblinded, single-center study evaluated the efficacy of venlafaxine XR in the treat- ment of chronic pain with associated depression diag- nosed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria”? For this study, 197 men and women were randomly recruited vvia referral by primary care physicians (PC's) for the treatment of depression, with or without pain. The severity of depression was determined using the 21- item Hamilton Rating Scale for Depression (HAM-D- 21)* The intensity of pain was assessed using the Visual Analogue Scale (VAS). Changes in QOL were evaluated in all patients, regardless of diagnosis, using, a 12-item self-assessment scale that required patients to rate their levet of satisfaction by choosing a number from 1 to 9 (ie, ranging from extremely dissatisfied to extremely satisfied)” Patients included in the study were adults 18 years of age or older who had previ- ously failed treatment with either TCAs or selective serotonin reuptake inhibitor (SSRIs) antidepressants ural of Therapeutics (2003) 105)320 Table 2. Pharmacokinetics of venlataxine overview. Bradley ot al * Chemistry: phenethylamine, racemic mixture (levo isomer NE and DA reuptake inhibitor and dextro isomer a 5 HT reuptake inhibitor) * Active metabolite: O-desmethy! venlafaxine (DV) ‘+ Mechanism of action (MOA): both parent and ODV ‘weak dopamine reuptake inhibitor (DARI) + Absorption: =92% ferotonin and norepinephrine reuptake inhibitor end + Metabolism: extensive hepatic phase | CYP45O 208 substrate (12.6% in systemic circulation) * Bioavailability (Fl: 45% + Elimination: renal (87% recovered =48 hours as 5% parent, 29% ODV, 26% conjugated, 27% minor metabolite) * Extended release: C,,,, = 150 ng/mL (parent), 260 agimL. [ODVI: Tings 5.5 hours (parent, 9 hours (ODV) + Absorption of extended release: same extent but slower rate compared with immediate release * Plasma protein binding (PPB): =30% (no protein-binding drug interactions) + Steady state: 3 days (parent and ODV} * Clearance (Cli: 1.21 Uivkg (parent) and 0.4 Lihvkg (ODV) total body clearance * Elimination half-life (t.29): 5 hours (parent), 11 hour (metabolite) + Volume of distribution (Vd): 7.5 hours (parent), 6.8 hours (metabolite) + Liver disease (substantial interpatient variance) cirrhosis: t,.25! inereased by 20% (parent) and 60% (ODV); CL, decreased by 50% (parent) and 30% (ODV) * Renal disease: if creatinine clearance (Cler) or glomerular fitration rate (GFR) = 10 to 70 mLimin, half life (ye4) increased by 80% (parent) and 40% (ODV\; CL, parent decreased by 25% and ODV, decreased by 0% + Hemodialysis patients: t/a, increased by 180% (parent); CL = 142% (ODV), decreased by 57% (parent) and 56% (oov) * PG Category: C {as of 1996, US Food and Drug Administration received no reports of adverse prognancy outcome involving the use of venlafaxine during gestation)? + Lactation: parent and ODV in breast milk” From Barkin RL, Foweett J: The management chalienges of chronic pain: the role af antidepressants. Am J Ther 2000;7-37-a7, Patients had chronic pain not caused by apparent psy- chologic factor for at least 3 months before study en- rollment. These pain patients included migraine head- ache, chronic back pain, chronic failed back pain, chronic regional pain syndrome (CRPS), reflex sym_ Table 3. Chronic pain syndromes fraquently encountered in primary care Low back pain and failed low back surgery syndrome” Cancer pain Fibromyalgia syndrome (FMS)* Neuropathic pain* Complex regional pain syndrame* Sickle cell pain Primary dysmenorthea* Chronic pelvic pain* Herpes simplex'zoster Postherpetic neuraigia* Trigeminal neuralgia® Atypical facial pain” Phantom limb pain (after amputation)* Burn pain Multiple sclerosis pain” Post laminectomy pain syndrome* “Responds to antidepraseants American Jouraal of Therapeutics (2003) 1065) pathic dystrophy (RSD), regional compartment syn- drome, or surgically repaired lumbosactal disc hernia- tions. All patients provided written informed consent to participate in the study. Patients were excluded from the study if they had a history of substance abuse, hypochondriasis, acute psychosis, organic brain syndrome, or somatization disorder. Venlafaxine treatinent was initiated after a washout period of at least 10 days from previously failed ant depressants, In addition, up to a -month washout petiod was required for fluoxetine due to its long half- life of the metabolite norfluoxetine (7-9 days) and plasma was washout period of 30 days." For the TCAs that have haif-lives up to 89 houts (for parent and metabolites) and plasma washout periods up to 18 days. Consideration for these patients on antide- pressants was provided by an extended washout pe- riod. For the first 3 days, venlafaxine immediate re- lease (IR) 12.5 mg was administered twice daily. This was followed by 3 days of treatment with venlafaxine IR 37.5 mg twice daily and then venlafaxine XR 373 mg once daily. The venlafaxine XR dosage was then titrated every 3 days to 75 mg, then followed by an- other 3 days to 130 mg or higher once daily. The ven- lafaxine XR dosages used are shown in Table 2. TheVenlafaxine for Chronie Pain With Major Depression i 1 Fe b i i FIGURE 1. Depression, combined male and female, mates. mean dose was 225 mg/d. The use of additional an- tidepressant or opiate/opioid analgesic agents was not permitted; for intermittent pain relief, COX I non- steroidal anti-inflammatory (NSAID) medications were permitted, ie: rofecoxib, if there were inflamma- tory indices of elevated erythrocyte sedimentation rate or cold reactive protein levels indicating an acute on: going inflammation process.”**** Patients received psychologic therapy (CBT), physical therapy (PT) (including water aerobics), and pain management education during this study. Each participant was diagnosed using the DSM 1Y criteria. The same physician, who was not blind to the diagnosis or treatment of the patient, administered se- rial Hamilton Rating Scale for depression continually throughout the study on an outpatient basis. The pa- tients then received follow-up evaluations weekly during the first month of the study and then biweekly during the second month. During months 3-12, pa- tients were evaluated monthly. Differences between ‘group means at initial evaluation and at the end of the study were determined using a repeated-measures analysis of variance at a 0105 level of significance. RESULTS A total of 186 patients who completed the study were included in the analysis. Baseline characteristics were i 6 : L @ 2s 2s ne Fost a * ms a FIGURE 4. Pain, combined male and female females. 3a gu fe Se FIGURE 3. Depression—select males. FIGURE 2. Depression—select fe- comparable between the depression-only patients and the patients with depression plus pain (Figs. 1-3). All patients met the criteria for major depression disorder ing DSM-IV criteria. Types of chronic pain include back pain, post surgical hip pain, osteoarthritis (OA) or fibromyalgia (FMS) in origin, extremity pain: CRPS/RSD, regional myofascial pain, carpal tunnel syndrome, migraines, and neuropathic pain Venlafaxine was generally well tolerated. Of the pa- tients who completed the study, 7% reported adverse effects, most commonly nausea, dizziness, and agita- tion. Eleven patients discontinued treatment owing to drug-related adverse effects that included nausea, anxiousness, agitation, and sexual side effects. None of the evaluation showed significant differences rela- tive to gender; therefore, data from men (Figs. 3 & 6) and women (Figs. 2 & 5) were collapsed for group analyses (Figs. 1 & 4). Treatment with venlafaxine XR for 1 year signifi cantly improved chronic pain as determined by the VAS. The mean baseline VAS score of the 73 patients with pain was 8.4 (Figs. 4-6); this improved to 34 after 1 year of treatment (P < 0.001), showing, long-term efficacy of venlafaxine XR as analgesic agent. Treatment with venlafaxine XR improved HAM-D™ scores from pretreatment baseline scores. Mean base- line HAM-D scores were similar for depression only and depression plus pain groups, 173 and 168, re- spectively (Figs. 1-3), The mean post-treatment scores is pu ‘Post RE Post FIGURE 5. Pain scores—pro and post FIGURE 6, Pain scores—pre and post males. American Journal of Therapeutics (2003) 10651322 of both groups were 89, as statistically significant im- provement (P < 0,001) from pretreatment baseline scores. Long-term efficacy of venlafaxine XR in the treatment of depression was shown in both the de- pression only and the depression plus pain groups In both the depression and the depression plus pain groups, QOL improved over the 1-year course of treat- ment with venlafaxine XR. Baseline QOL scores were similar for patients with depression only (20.2) and with depression plus pain (20.6; Figs. 1-3). The mean post-treatment scores for both groups were also simi- lar: 86.5 for patients with depression plus pain. This improvement was statistically significant for both ‘groups (P < 0.001), DISCUSSION These data suggest, from this unblended open study, the efficacy of a dual action 5-HT/NE antidepres: sant of venlafaxine XR in the treatment of chtonic pain andl depression over a 1-year period. These find- ings support previous reports that antidepres- sants that modulated serotonergic and noradre- nergic systems are effective in the treatment of chronic pain in non-depressed patients.“** "2" Both sero. tonergic and noradrenergic impairments have been described in both, migraine and fibromyalgia syn- drome (FMS).9102251 The ventromedial hypothalamus controls energy metabolism as well as regulating glucocorticoids and ther stress hormones. The neuromodulator serotonin, and tryptophan from which it derives, are both noted as being significantly reduced in FMS patients, and this has been shown to correlate with pain symptoms." Substance P is normally released by spinal cord tissues (afferent neurons) as a response to pain- ful stimuli; therefore excessive levels would increase pain perception. In addition serotonin may exert a potentiating effect ‘on the endogenous opioid system, another important component of analgesia.“ Thus, the direct and in- direct effects of both serotonin and norepinephrine seem to be important factors in analgesia Unlike other dual mechanism antidepressants, ver: lafaxine may have unique potential as an analgesic because itis structurally similar to the analgesic agent tramadol?” Tramadol supraspinally modulates the 1-opiate receptors and spinally tramadol blocks reuptake of 5-HT and NE modulating the descending pathways leading to modulation marginal zone lami= nae T substantia gelatinosa on laminae I on dorsal hom of the spinal cord.” Although both agents act Amen al of Therapeutics (2003) 105) Jou Bradley et al mainly through the serotonin, norepinephrine, and opioid system," venlafaxine, however, is a more ef- fective SNRI than tramadol; animal studies have shown that analgesic effects of venlafaxine are medi- ated through x- and 8-opioid receptors, subtypes dif- ferent from those of tramadol. Thus, both direct effects on serotonin and norepinephrine systems and indirect effects on opioid systems are probably important features of the analgesic mechanism of venlafaxine. Venlafaxine is low plasma protein bound 25 to 30%) and possesses no clinically relevant CYP 450 induction or inhibition drug interactions (see Table 1.0 The data in this study suggest corroboration with previous evaluations of the long-term efficacy of ven- Tafaxine as an antidepressant agent. Venlafaxine specificity for serotonergic and noradrenergic reup- take sites confers a favorable side-effect profile'75"""= and may therefore increase adherence to long-term pharmacotherapy." For patients who have both depression and chronic pain, treating both disorders with only one agent administered once daily may also increase compliance" and improve treatment out- come." Physiologic and psychologic symptoms of both anxiety and depression have prominent decre- mental changes concurrent with venlafaxine treat- ment, Patients in this study perceived their QOL as significantly improved with the simultaneous treat- ment of depression and chronic pain. CONCLUSIONS Results from this study suggest the long-term analge- sic and antidepressant efficacy of venlafaxine XR in patients with major depressive disorder and chronic pain. Further large-scale studies are needed both to confirm these findings and to evaluate the efficacy of venlafaxine as an analgesic agent for patients with de- pression and chronic pain as concurrent disorders, REFERENCES 1. Barkin R, Fawcett J. The management challenges of chronic pain: the ole of antidepressants. Ant | Ther. 2000; 737-47. 2. France RD. Psychiatric aspects of pain, Clin J Poin: 1989,5,Suppl 2) 535-512 3. Ruoff GE. Depression in the patient with chronic pain. | Fam Pract. 198643(Suppl)S25-SH, 4. Gallagher RM, Venna 5. 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