Combination strategies for pain management

Raffa, Robert B.; Clark-Vetri, Rachel; Tallarida, Ronald J.; Wertheimer, Albert I.

doi:10.1517/eoph.4.10.1697.22313

Cited by 3 publications

(2 citation statements)

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“…In a study conducted in advanced cancer patients receiving a stable dose of opioids, the addition of 5 g of acetaminophen daily resulted in significant improvement in pain compared with placebo [42]. Combination opioid products confer better pain control than do individual components given at the same doses, owing to the concept of additive synergistic analgesia [43][44][45]. However, whether acetaminophen exhibits a ceiling effect at higher doses is unknown [46][47][48], and such an effect could explain the lower MEDD-hydrocodone ratio for higher doses of hydrocodone.…”

Section: Cmementioning

confidence: 99%

The Opioid Rotation Ratio of Hydrocodone to Strong Opioids in Cancer Patients

et al. 2014

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Purpose. Cancer pain management guidelines recommend initial treatment with intermediate‐strength analgesics such as hydrocodone and subsequent escalation to stronger opioids such as morphine. There are no published studies on the process of opioid rotation (OR) from hydrocodone to strong opioids in cancer patients. Our aim was to determine the opioid rotation ratio (ORR) of hydrocodone to morphine equivalent daily dose (MEDD) in cancer outpatients. Patients and Methods. We reviewed the records of consecutive patient visits at our supportive care center in 2011–2012 for OR from hydrocodone to stronger opioids. Data regarding demographics, Edmonton Symptom Assessment Scale (ESAS), and MEDD were collected from patients who returned for follow‐up within 6 weeks. Linear regression analysis was used to estimate the ORR between hydrocodone and MEDD. Successful OR was defined as 2‐point or 30% reduction in the pain score and continuation of the new opioid at follow‐up. Results. Overall, 170 patients underwent OR from hydrocodone to stronger opioid. The median age was 59 years, and 81% had advanced cancer. The median time between OR and follow‐up was 21 days. We found 53% had a successful OR with significant improvement in the ESAS pain and symptom distress scores. In 100 patients with complete OR and no worsening of pain at follow‐up, the median ORR from hydrocodone to MEDD was 1.5 (quintiles 1–3: 0.9–2). The ORR was associated with hydrocodone dose (r = −.52; p < .0001) and was lower in patients receiving ≥40 mg of hydrocodone per day (p < .0001). The median ORR of hydrocodone to morphine was 1.5 (n = 44) and hydrocodone to oxycodone was 0.9 (n = 24). Conclusion. The median ORR from hydrocodone to MEDD was 1.5 and varied according to hydrocodone dose.

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Section: Cmementioning

confidence: 99%

The Opioid Rotation Ratio of Hydrocodone to Strong Opioids in Cancer Patients

et al. 2014

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“…Advantages and potential disadvantages of this strategy have been reviewed (e.g. Raffa 2001;Raffa et al 2003). In relation to neuropathic pain, the major advantages could be facilitation of prescribing and enhanced compliance, broader coverage of diverse pain types, decreased side effects, and a possible synergistic analgesic interaction.…”

Section: Combinationsmentioning

confidence: 99%

Dysesthetic Vulvodynia

Encyclopedia of Pain

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Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets, in a murine model of cancer-induced bone pain

González-Rodríguez

Poras

Menéndez

et al. 2017

Scandinavian Journal of Pain

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AbstractBackgroundThe first line pharmacological treatment of cancer pain is morphine and surrogates but a significant pain relief and a reduction of the side-effects of these compounds makes it necessary to combine them with other drugs acting on different targets. The aim of this study was to measure the antinociceptive effect on cancer-induced bone pain resulting from the association of the endogenous opioids enkephalin and non-opioid analgesic drugs. For this purpose, PL265 a new orally active single dual inhibitor of the two degrading enkephalins enzymes, neprilysin (NEP) and aminopeptidase N (APN) was used. It strictly increased the levels of enkephalin at their sites of releases. The selected non-opioid compounds are: gabapentin, A-317491 (P2X3 receptor antagonist), ACEA (CB1 receptor antagonist), AM1241 (CB2 receptor antagonist), JWH-133 (CB2 receptor antagonist), URB937 (FAAH inhibitor), and NAV26 (Nav1.7 channel blocker).MethodsExperiments. Experiments were performed in 5–6 weeks old (26–33g weight) C57BL/6 mice. Cell culture and cell inoculation. B16-F10 melanoma cells were cultured and when preconfluent, treated and detached. Finally related cells were resuspended to obtain a concentration of 2×106 cells/100μL. Then 105 cells were injected into the right tibial medullar cavity. Control mice were treated by killed cells by freezing. Behavioural studies. Thermal withdrawal latencies were measured on a unilatered hot plate (UHP) maintained at 49±0.2 °C.Mechanical threshold values were obtained by performing the von Frey test using the “up and down” method. To evaluate the nature (additive or synergistic) of the interactions between PL265 and different drugs, an isobolographic analysis following the method described by Tallarida was performed.ResultsThe results demonstrate the ability of PL265, a DENKI that prevents the degradation of endogenous ENKs, to counteract cancer-induced bone thermal hyperalgesia in mice, by exclusively stimulating peripheral opioid receptors as demonstrated by used of an opioid antagonist unable to enter the brain. The development of such DENKIs, endowed with druggable pharmacokinetic characteristics, such as good absorption by oral route, can be considered as an important step in the development of much needed novel antihyperalgesic drugs. Furthermore, all the tested combinations resulted in synergistic antihyperalgesic effects. As shown here, the greatest synergistic antinociceptive effect (doses could be lowered by 70%) was produced by the combination of PL265 with the P2X3 receptor antagonist (A-317491), cannabinoid CB1 receptor agonist (exogenous, ACEA and endogenous URB937-protected-AEA) and Nav1.7 blocker (NAV26) whose mechanism of action involves the direct activation of the enkephalinergic system.ConclusionsThese multi-target-based antinociceptive strategies using combinations of non-opioid drugs with dual inhibitors of enkephalin degrading enzymes may bring therapeutic advantages in terms of efficacy and safety by allowing the reduction of doses of one of the compounds or of both, which is of the utmost interest in the chronic treatment of cancer pain.ImplicationsThis article presents synergistic antinociceptive effect produced by the combination of PL265 with non-opioid analgesic drugs acting via unrelated mechanisms. These multi-target-based antinociceptive strategies may bring therapeutic advantages by allowing the reduction of doses, which is of great interest in the chronic treatment of cancer pain.

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Combination strategies for pain management

Cited by 3 publications

References 0 publications

The Opioid Rotation Ratio of Hydrocodone to Strong Opioids in Cancer Patients

The Opioid Rotation Ratio of Hydrocodone to Strong Opioids in Cancer Patients

Dysesthetic Vulvodynia

Synergistic combinations of the dual enkephalinase inhibitor PL265 given orally with various analgesic compounds acting on different targets, in a murine model of cancer-induced bone pain

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