Rational multidrug therapy in the treatment of neuropathic pain

Backonja, Misha-Miroslav; Irving, Gordon; Argoff, Charles

doi:10.1007/s11916-006-0007-1

Cited by 78 publications

(51 citation statements)

References 27 publications

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“…It remains speculative whether aggressive, pre-emptive analgesic approaches can reduce progression to chronic PMS. Growing awareness of sensitization within the peripheral and central nervous system following high levels of nociceptive activity has led to empiric multimodal management of other procedure-related neuropathic pain states (NCCN Category 2B) [49,50].…”

Section: Frozen Shouldermentioning

confidence: 99%

Barriers to rehabilitation following surgery for primary breast cancer

Cheville

Tchou

2007

Journal of Surgical Oncology

221

171

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Surgery is a mainstay of primary breast cancer therapy. Alterations in surgical technique have reduced normal tissue injury, yet pain and functional compromise continue to occur following treatment. A tenuous evidence base bolstered by considerable expert opinion suggests that early intervention with conventional rehabilitative modalities can reduce surgery-associated pain and dysfunction. Barriers to the timely rehabilitation of functionally morbid sequelae are discussed at length in this article. Barriers arise from a wide range of academic, human, logistic, and financial sources. Despite obstacles, expeditious and effective post-surgical rehabilitation is being regularly delivered to breast cancer patients at many institutions. This experience has given rise to anecdotal information on the management of common sequelae that may undermine function. The epidemiology, pathophysiology, and management of these sequelae are outlined in this article with an emphasis on the caliber of supporting evidence. Myofascial dysfunction, axillary web syndrome, frozen shoulder, lymphostasis, post-mastectomy syndrome, and donor site morbidity following breast reconstruction are addressed. A critical need for more definitive evidence to guide patient management characterizes the current treatment algorithms for surgical sequelae.

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Section: Frozen Shouldermentioning

confidence: 99%

Barriers to rehabilitation following surgery for primary breast cancer

Cheville

Tchou

2007

Journal of Surgical Oncology

221

171

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“…The current treatments for neuropathic pain achieve some relief; however, there remains significant room for improvement (Harden and Cohen, 2003). An intriguing question is whether increased relief can be obtained by using rational combinations of drugs (Gilron and Max, 2005;Backonja et al, 2006). The optimization of a rational drug combination represents a major challenge, because it involves not only the selection of the appropriate combination of drugs, each with a different mechanism of action, but also the optimal doses for using those drugs.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic–Pharmacodynamic Analysis of the Static Allodynia Response to Pregabalin and Sildenafil in a Rat Model of Neuropathic Pain

Bender¹,

Florian²,

Bramwell³

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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The objective of this study was to develop a pharmacokineticpharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mg⅐kg Ϫ1 ⅐h Ϫ1 ; 3) a 2-h pregabalin infusion at 10 mg⅐kg Ϫ1 ⅐h Ϫ1 ; 4) a 2.2-mg loading dose ϩ 12 mg⅐kg Ϫ1 ⅐min Ϫ1 infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mg⅐kg Ϫ1 ⅐h Ϫ1 with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mg⅐kg Ϫ1 ⅐h with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration-response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC 50 of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC 50 , whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.Neuropathic pain represents an area of largely unmet medical need with significant impact on health-related quality of life (Jensen et al., 2007). At present, neuropathic pain is treated by using a variety of different medications (e.g., antidepressants, gabapentin, pregabalin, opioids) with mechanisms of action that include inhibiting serotonin and norepinephrine uptake, altering ion channel transport, and occupying N-methyl-D-aspartate receptors (Nurmikko and Haanpä ä , 2005;Chong and Brandner, 2006;Francis et al., 2006;Gilron et al., 2006;Jackson 2006;Stillman, 2006). The current treatments for neuropathic pain achieve some relief; however, there remains significant room for improvement (Harden and Cohen, 2003). An intriguing question is whether increased relief can be obtained by using rational combinations of drugs (Gilron and Max, 2005;Backonja et al., 2006). The optimization of a rational drug combination represents a major challenge, because it involves not only the selection of the appropriate combination of drugs, each with a different mechanism of action, but also the optimal doses for using those drugs. The overall goal of this project was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model describing the interaction between pregabalin and sildenafil in rats.Pregabalin is a ligand to the ␣ 2 ␦ subunit of the voltagegated calcium channel. Avid binding at this site reduces calcium influx at...

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“…Assessment of pain and comorbidities Investigate pain mechanism (quantitative sensory testing if possible) Drug choices based upon mechanisms Start at the low end of recommended dose ranges and titrate Reassess for response (2 point reduction on a numerical rating scale of 0-10 for example) Assess response also based upon improved function, activities of daily living, and quality of life Monitor for drug side effects If side effects supervene with partial response rotate to a drug in the same class, if not available add a drug from another class If failure to respond at recommended doses, add an analgesic from a different class Add one drug at a time, titrate to recommended therapeutic range before adding a second drug Do not add a second drug from the same class (i.e., 2 TCAs or 2 opioids) Drug choices should include consideration of drug interactions, comorbidities, comedications other than analgesics, patient preferences, and symptoms [99] …”

Section: Discussionmentioning

confidence: 99%

“…The rationale behind drug combinations is that multiple mechanisms generate neuropathic pain and it is unlikely that a single drug will effectively treat these multiple mechanisms. The best experience with single therapy is partial relief in a subset of patients [99]. Combinations of drugs with different modes of action would be expected to further improve pain.…”

Section: Multiple Drug Therapymentioning

confidence: 99%