Ultralow Dose of Naloxone as an Adjuvant to Intrathecal Morphine Infusion Improves Perceived Quality of Sleep but Fails to Alter Persistent Pain

Block, Linda; Lundborg, Christopher; Bjersing, Jan; Dahm, Peter; Hanssoń, Elisabeth; Biber, Björn

doi:10.1097/ajp.0000000000000200

Cited by 19 publications

(18 citation statements)

References 57 publications

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“…One trial, with risk of bias relating to blinding and incomplete outcome data, evaluated intravenous calcitonin for phantom limb pain in 20 patients, and found no effect up to 48 h after infusion compared with saline. Another trial, with no clear evidence of risk of bias, evaluated low doses of oral/or intravenous naloxone as a supplement in 12 patients whose severe CPSP was already managed by continuous intrathecal morphine administration. No evidence of an effect on pain relief was found after two 3‐week sessions on differing doses of the drug across a 9‐week period…”

Section: Resultsmentioning

confidence: 99%

Systematic review of management of chronic pain after surgery

Wylde

Dennis

Beswick

et al. 2017

British Journal of Surgery

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BackgroundPain present for at least 3 months after a surgical procedure is considered chronic postsurgical pain (CPSP) and affects 10–50 per cent of patients. Interventions for CPSP may focus on the underlying condition that indicated surgery, the aetiology of new‐onset pain or be multifactorial in recognition of the diverse causes of this pain. The aim of this systematic review was to identify RCTs of interventions for the management of CPSP, and synthesize data across treatment type to estimate their effectiveness and safety.Methods MEDLINE, Embase, PsycINFO, CINAHL and the Cochrane Library were searched from inception to March 2016. Trials of pain interventions received by patients at 3 months or more after surgery were included. Risk of bias was assessed using the Cochrane risk‐of‐bias tool.ResultsSome 66 trials with data from 3149 participants were included. Most trials included patients with chronic pain after spinal surgery (25 trials) or phantom limb pain (21 trials). Interventions were predominantly pharmacological, including antiepileptics, capsaicin, epidural steroid injections, local anaesthetic, neurotoxins, N‐methyl‐d‐aspartate receptor antagonists and opioids. Other interventions included acupuncture, exercise, postamputation limb liner, spinal cord stimulation, further surgery, laser therapy, magnetic stimulation, mindfulness‐based stress reduction, mirror therapy and sensory discrimination training. Opportunities for meta‐analysis were limited by heterogeneity. For all interventions, there was insufficient evidence to draw conclusions on effectiveness.ConclusionThere is a need for more evidence about interventions for CPSP. High‐quality trials of multimodal interventions matched to pain characteristics are needed to provide robust evidence to guide management of CPSP.

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Section: Resultsmentioning

confidence: 99%

Systematic review of management of chronic pain after surgery

Wylde

Dennis

Beswick

et al. 2017

British Journal of Surgery

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“…Furthermore, sleep deprivation decreases morphine analgesia, possibly by decreasing descending pain inhibitory activity and by increasing descending pain facilitatory activity [97]. Conversely, sleep improves from intrathecal morphine infusion in patients with severe pain [98]. A recent meta-analysis showed that sleep disturbance is associated with increase in markers of systemic inflammation [99].…”

Section: Discussionmentioning

confidence: 97%

The effect of sleep deprivation on pain perception in healthy subjects: a meta-analysis

et al. 2015

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“…Our group performed a pilot study consisting of eleven patients with persistent pain following multiple surgeries, who were being treated with continuous intrathecal morphine administration; in the study, ultralow-dose naloxone was administered via the same route [118]. The reason for not using the above discussed triple combination is that we wanted the option to investigate the effect of each agent individually in vivo.…”

Section: Clinical Applicationsmentioning

confidence: 99%

Glial dysfunction and persistent neuropathic postsurgical pain

Block

2016

Scandinavian Journal of Pain

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AbstractBackgroundAcute pain in response to injury is an important mechanism that serves to protect living beings from harm. However, persistent pain remaining long after the injury has healed serves no useful purpose and is a disabling condition. Persistent postsurgical pain, which is pain that lasts more than 3 months after surgery, affects 10–50% of patients undergoing elective surgery. Many of these patients are affected by neuropathic pain which is characterised as a pain caused by lesion or disease in the somatosen-sory nervous system. When established, this type of pain is difficult to treat and new approaches for prevention and treatment are needed.A possible contributing mechanism for the transition from acute physiological pain to persistent pain involves low-grade inflammation in the central nervous system (CNS), glial dysfunction and subsequently an imbalance in the neuron–glial interaction that causes enhanced and prolonged pain transmission.AimThis topical review aims to highlight the contribution that inflammatory activated glial cell dysfunction may have for the development of persistent pain.MethodRelevant literature was searched for in PubMed.Results Immediately after an injury to a nerve ending in the periphery such as in surgery, the inflammatory cascade is activated and immunocompetent cells migrate to the site of injury. Macrophages infiltrate the injured nerve and cause an inflammatory reaction in the nerve cell. This reaction leads to microglia activation in the central nervous system and the release of pro-inflammatory cytokines that activate and alter astrocyte function. Once the astrocytes and microglia have become activated, they participate in the development, spread, and potentiation of low-grade neuroinflammation. The inflammatory activated glial cells exhibit cellular changes, and their communication to each other and to neurons is altered. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocyte dysfunction can be experimentally restored using the combined actions of a μ–opioid receptor agonist, a μ–opioid receptor antagonist, and an anti-epileptic agent. To find these agents we searched the literature for substances with possible anti-inflammatory properties that are usually used for other purposes in medicine. Inflammatory induced glial cell dysfunction is restorable in vitro by a combination of endomorphine-1, ultralow doses of naloxone and levetiracetam. Restoring inflammatory-activated glial cells, thereby restoring astrocyte-neuron interaction has the potential to affect pain transmission in neurons. ConclusionSurgery causes inflammation at the site of injury. Peripheral nerve injury can cause low-grade inflammation in the CNS known as neuroinflammation. Low-grade neuroinflammation can cause an imbalance in the glial-neuron interaction and communication. This renders neurons more excitable and pain transmission is enhanced and prolonged. Astrocytic dysfunction can be restored in vitro by a combination of endomorphin-1, ultralow doses of naloxone and levetiracetam. This restoration is essential for the interaction between astrocytes and neurons and hence also for modulation of synaptic pain transmission.ImplicationsLarger studies in clinical settings are needed before these findings can be applied in a clinical context. Potentially, by targeting inflammatory activated glial cells and not only neurons, a new arena for development of pharmacological agents for persistent pain is opened.

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Ultralow Dose of Naloxone as an Adjuvant to Intrathecal Morphine Infusion Improves Perceived Quality of Sleep but Fails to Alter Persistent Pain

Abstract: Supplemental Digital Content is available in the text.

Cited by 19 publications

References 57 publications

Systematic review of management of chronic pain after surgery

Systematic review of management of chronic pain after surgery

The effect of sleep deprivation on pain perception in healthy subjects: a meta-analysis

Glial dysfunction and persistent neuropathic postsurgical pain

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