Pain relief from nonpharmacological interventions in the intensive care unit: A scoping review.

AIMS AND OBJECTIVES: To describe what is known from the existing literature on nonpharmacological interventions targeting pain in patients admitted to the ICU. BACKGROUND: Patients receiving intensive care nursing are exposed to a wide range of pain provoking tissue damage, diseases, surgery and other medical procedures in addition to the pain caused by nursing care procedures. The present shift to light sedation to improve patient outcomes and comfort underscores the need for effective pain management. Opioids are the mainstay for treating pain in the ICUs, whereas nonpharmacological treatments are understudied and possibly under-used. METHOD: A scoping review was undertaken using five of the six steps in the Arksey and O´Malley framework: (a) identification of the research question, (b) identification of relevant studies, (c) study selection, (d) charting the data and (e) collating, summarising and reporting the results. CINAHL, MEDLINE, PubMed, BMJ Best Practice, British Nursing Index and AMED databases were searched using relevant keywords to capture extensive evidence. Data were analysed using the six-step criteria for scoping reviews suggested by Arksey and O´Malley for data extraction. To ensure quality and transparency, we enclosed the relevant Equator checklist PRISMA. RESULTS: Our search yielded 10,985 articles of which 12 studies were included. Tools for pain assessments were VAS, NRS, ESAS and BPS. Interventions explored were hypnosis, simple massage, distraction, relaxation, spiritual care, harp music, music therapy, listening to natural sounds, passive exercise, acupuncture, ice packs and emotional support. Reduction in pain intensity was conferred for hypnosis, acupuncture and natural sounds. CONCLUSION: The findings support further investigations of acupuncture, hypnosis and listening to natural sounds. RELEVANCE TO CLINICAL PRACTICE: The main finding suggests the use of comprehensive multimodal interventions to investigate the effects of nonpharmacological treatment protocols on pain intensity, pain proportion and the impact on opioid consumption and sedation requirements.

The association between Modic changes and pain during 1-year follow-up in patients with lumbar radicular pain.

OBJECTIVE: To examine whether Modic changes influence pain during a 1-year follow-up in patients with lumbar radicular pain. MATERIALS AND METHODS: A total of 243 patients with lumbar radicular pain due to disc herniation were recruited from two hospitals in Norway and followed up at 6 weeks, 6 months, and 12 months. On baseline lumbar magnetic resonance images, two observers independently evaluated Modic changes (types I-III; craniocaudal size 0-3). Outcomes were sensory pain (McGill Pain Questionnaire), back and leg pain (visual analogue scale, VAS). Association between Modic type and outcomes was explored with a mixed model and then by two-way analysis of variance (ANOVA) at each time point with Modic and treatment groups (surgical, n = 126; nonsurgical, n = 117) as fixed factors, adjusted for disc degeneration, age, sex, smoking, and duration of radicular pain. Modic size was also analyzed using ANOVA. RESULTS: Pain scores had decreased significantly at 1-year follow-up. Modic type was significantly related to McGill sensory scores (mixed model: p = 0.014-0.026; ANOVA: p = 0.007 at 6 weeks), but not to VAS back pain or VAS leg pain scores. At 6 weeks, the mean McGill sensory score was higher in Modic I than in Modic II-III patients (p = 0.003) and in patients without Modic changes (p = 0.018). Modic size L1-S1 was not associated with pain outcomes. CONCLUSION: Patients with lumbar radicular pain have a substantial pain reduction during 1-year follow-up, but Modic type I changes may imply a slower initial decrease in sensory pain.

Measuring pain intensity through physical interaction in an experimental model of cold-induced pain: A method comparison study.

OBJECTIVES: Assessment of pain is challenging given its subjective nature. Standard pain assessment tools have limitations. We aimed to compare the verbal numeric rating scale (NRS) and Grasp, a novel handheld electronic device that reports pain by squeezing. METHODS: To compare Grasp and NRS, healthy adult volunteers were invited to undergo two subsequent standardised tests of cold-triggered pain using a cold pressor test (CPT) at a temperature of 3°C. Pain intensity was in a randomised manner reported by NRS (scale 0-10) or by squeezing Grasp (0-3 V) during the two CPTs. A third CPT was performed 1 to 14 days later where subjects reported pain by Grasp a second time in order to study the association of repeated Grasp measurements. Acceptable association was a priori considered as mean Kendall's τ-b coefficient (τ-b) ≥ 0.7. The subjects reported their experience of using Grasp in a purpose-made questionnaire. RESULTS: In total, 102 subjects were included, and 96 subjects (56 females) completed all three tests. The association of pain intensity reported by Grasp and NRS was moderate with a mean τ-b of 0.53 (95% confidence interval [CI] 0.47-0.58). The association between the repeated Grasp measurements was weak with a mean τ-b of 0.43 (95% CI 0.37-0.48). Most subjects reported that Grasp was intuitive and easy to use. CONCLUSIONS: Pain intensity reported by squeezing Grasp did not show acceptable association with pain intensity reported by NRS during CPTs. The association between pain intensity reported by Grasp during two CPTs on separate days was weak. Further improvements of the Grasp ball are needed before use in clinical settings.

Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu 1 gene: evidence of a sex and genotype interaction.

Earlier studies have shown that the single nucleotide polymorphism (SNP) A118G (rs1799971) in the opioid receptor mu 1 (OPRM1) gene may affect pain sensitivity. In the present study we investigated whether the A118G SNP could predict clinical outcome regarding progression of pain intensity and disability in patients with low back pain and sciatica after lumbar disc herniation. Patients (n = 258) with lumbar disc herniation and sciatic pain, all European-Caucasian, were recruited from two hospitals in Norway. Pain and disability were rated on a visual analog scale (VAS), by McGill Sensory Questionnaire and by Oswestry Disability Index (ODI) over a 12 months period. The data revealed a significant interaction between sex and A118G genotype regarding the pain intensity during the 12 months (VAS, p = 0.002; McGill, p = 0.021; ODI, p = 0.205, repeated-measures ANOVA). We found that */G women had a slower recovery rate than the */G men. Actually, the */G women had 2.3 times as much pain as the */G men 12 months after the disc herniation (VAS, p = 0.043, one-way ANOVA; p = 0.035, Tukey HSD). In contrast, the A/A women and A/A men seemed to have almost exactly the same recovery rate. The present data suggest that OPRM1 G allele increases the pain intensity in women, but has a protective effect in men the first year after disc herniation.

[Long-lasting low back pain and MRI changes in the intervertebral discs]. / Langvarige korsryggssmerter og MR-forandringer i ryggvirvlene.

BACKGROUND: Although low back pain is usually temporary, some patients do not recover and need treatment. Therefore, it is important to uncover causal and contributing factors. Here we give an overview of recent research on MRI findings and genetic factors that may be important for development of long-lasting low back pain. MATERIAL AND METHODS: A non-systematic search in PubMed and EMBASE was performed. The relevant research articles identified, as well as the authors' knowledge of the field formed the basis for this review. RESULTS: It is generally accepted that low back pain often stems from intervertebral discs, facet joints and lumbar multifundi muscles. However, it is also known that many patients with pronounced disc degeneration have so-called Modic changes, i.e. MRI changes in bone marrow close to the vertebral endplates. Several recent studies have shown an association between such changes and pain. It has also been demonstrated that patients with Modic changes and low back pain often have concomitant inflammation and growth of nociceptive nerve fibers into the endplates. To which extent this occurs, may be partly based on genetics. INTERPRETATIONS: Genetic factors may contribute to low back pain. New knowledge about genetic factors and Modic changes can create a basis for better diagnostics and more specific treatment of patients with long-lasting low back pain.

Females report higher postoperative pain scores than males after ankle surgery.

OBJECTIVES: The majority of patients experience moderate-to-intense pain following ankle surgery. Early, adequate treatment of postoperative pain is desirable for optimal pain relief, which in turn may facilitate optimal pulmonary function, normal respiration pattern, rehabilitation and prevention of a chronic pain condition. In this retrospective study, we aimed to identify possible predictors of moderate-to-intense postoperative pain while in the Post Anaesthesia Care Unit (PACU) in patients operated for ankle fractures. MATERIALS AND METHODS: Social demographics and clinical characteristics from admission throughout the stay in the PACU were collected from the hospital patient record system in retrospect. Pain was assessed using a Visual Analogue Scale (VAS) or a verbal Numeric Rating Scale (vNRS). A VAS/vNRS score 4-6 was classified as moderate and 7-10 as intense pain. Other factors which were investigated were time from ankle fracture to surgery, anaesthetic procedure, pre-, per- and postoperative medical treatment, radiological classification, complexity of fracture, operative technique, and time using tourniquet procedure. RESULTS: Data from 336 patients who underwent surgery to repair an ankle fracture between January 2009 and December 2010 were analysed. None of the following variables had a statistically significant effect on pain; age, weight, smoking, timeframe from fracture to operation, type of anaesthesia, opioids given peroperatively, complexity of the fracture, operation technique or tourniquet inflation procedure. Female sex predicted moderate-to-intense postoperative pain in the PACU with odds ratio 2.31 (95% confidence interval 1.39-3.86), P=0.001. As far as we know, this is the first study to show a sex difference in reporting pain in the first hours after surgery for ankle fracture. CONCLUSION: Female patients operated for ankle fracture report higher pain-intensity-score than male patients while in the PACU. IMPLICATIONS: Our findings suggest that treatment strategies to prevent high peaks of pain should particularly target women operated for an ankle fracture.

Long-term potentiation in spinal nociceptive systems--how acute pain may become chronic.

Chronic pain is a major problem since it is difficult to treat and the understanding of the underlying neurobiology is sparse. The mechanisms underpinning the transition of acute into chronic pain remain unclear. However, long-term potentiation (LTP) in spinal nociceptive systems may be one such mechanism. Here, we briefly review the literature regarding LTP in spinal nociceptive systems including our own data on LTP in deep convergent nociceptive neurons. Furthermore, we discuss the role of this phenomenon in understanding the neurobiology of chronic pain and the possible therapeutic implications.

[Molecular mechanisms in acute and chronic pain states]. / Molekylaere mekanismer ved akutte og kroniske smerter.

BACKGROUND: Pain is a sense necessary for survival and has a complex neurobiological basis. In recent years a powerful battery of techniques has been developed to unravel the mechanisms by which painful stimuli are transduced and processed both in the acute and pathological state. MATERIAL AND ANALYSIS: We review the literature with special emphasis on recent discoveries regarding the molecular transduction mechanisms in nociceptors and novel molecular and cellular mechanisms underlying the spinal processing of painful stimuli. RESULTS AND INTERPRETATION: The mechanisms by which sensory neurons initiate hyperalgesia and touch-evoked pain (allodynia) have been addressed particularly successfully in recent studies. The rich variety of key molecular players that have emerged in physiological and pathophysiological pain states reflects the sophistication and uniqueness of this important sense. This is good news for both the pain scientist and the pain clinician since it increases the intellectual challenge and provides a plethora of targets for novel analgesics and treatments.

Increased spinal N-methyl-D-aspartate receptor function after 20 h of carrageenan-induced inflammation.

Spinal N-methyl-D-aspartate (NMDA) receptors are thought to be important in states of central hyperexcitability induced by e.g. inflammation or painful neuropathies. The carrageenan model of inflammatory pain has been and still is widely used as is the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5) to investigate NMDA receptor function. Here we present two novel findings using electrophysiological technique: the NMDA receptor function in the spinal cord is increased following 20 h of carrageenan-induced inflammation and further that only the D-isomer of AP5 is active in the spinal cord. Exogenous NMDA (0.5 and 5 nmol) applied onto the dorsal spinal cord produced a significantly greater facilitation and D-AP5 (1.25 micromol) a significantly greater inhibition of the C-fibre evoked response of the wide dynamic range (WDR) neurones studied in carrageenan (20 h after injection) compared to control rats. The present and two recent studies suggest central changes are different and possibly greater in the later (20 h) compared to the earlier (2-6 h) phase of carrageenan-induced inflammation. In conclusion, 20 h of carrageenan-induced inflammation increases the function of spinal NMDA receptor involved in nociceptive transmission and in addition the D-isomer of AP5 should be used when NMDA receptor antagonism is wanted in the spinal cord.

Natural noxious stimulation can induce long-term increase of spinal nociceptive responses.

It is conceivable that plasticity in pain control systems and chronic pain may be due to mechanisms similar to learning. Long-term potentiation (LTP) in the hippocampus is often studied as a model of learning and memory. It has recently been shown that long-term excitation may be induced in single wide dynamic range (WDR) neurones in the spinal dorsal horn of rats after tetanic stimulation to the sciatic nerve. The present study shows that similar long-term changes can also be induced by a severe natural stimulus. Single unit extracellular recordings were made in urethane anaesthetized rats and the firing responses of WDR neurones evoked by a single electrical stimulus to the peripheral nerve were recorded every 4 min. After repeated crushing of tissue (including bone) corresponding to the receptive field of the WDR neurones (the conditioning stimulus) followed by a proximal total peripheral nerve block, the C-fibre evoked responses were increased (P < 0.001) for a 3 h observation period compared with baseline responses and control animals. In control animals the nerve block was applied before the conditioning stimulus. We suggest that a long-term increase of the excitability of WDR neurones may be important for the development of long lasting and chronic pain disorders after an acute but severe noxious stimulus.

Role of IL1A rs1800587, IL1B rs1143627 and IL1RN rs2234677 genotype regarding development of chronic lumbar radicular pain; a prospective one-year study.

Previous studies indicate that lumbar radicular pain following disc herniation may be associated with release of several pro-inflammatory mediators, including interleukin-1 (IL1). In the present study, we examined how genetic variability in IL1A (rs1800587 C>T), IL1B (rs1143627 T>C) and IL1RN (rs2234677 G>A) influenced the clinical outcome the first year after disc herniation. Patients (n = 258) with lumbar radicular pain due to disc herniation were recruited from two hospitals in Norway. Pain and disability were measured by visual analogue scale (VAS) and Oswestry Disability Index (ODI) over a 12 month period. The result showed that patients with the IL1A T allele, in combination with the IL1RN A allele had more pain and a slower recovery than other patients (VAS p = 0.049, ODI p = 0.059 rmANOVA; VAS p = 0.003, ODI p = 0.050 one-way ANOVA at 12 months). However, regarding the IL1B/IL1RN genotype, no clear effect on recovery was observed (VAS p = 0.175, ODI p = 0.055 rmANOVA; VAS p = 0.105, ODI p = 0.214 one-way ANOVA at 12 months). The data suggest that the IL1A T/IL1RN A genotype, but not the IL1B T/IL1RN A genotype, may increase the risk of a chronic outcome in patients following disc herniation.

The DQB1 *03:02 HLA haplotype is associated with increased risk of chronic pain after inguinal hernia surgery and lumbar disc herniation.

Neuropathic pain conditions are common after nerve injuries and are suggested to be regulated in part by genetic factors. We have previously demonstrated a strong genetic influence of the rat major histocompatibility complex on development of neuropathic pain behavior after peripheral nerve injury. In order to study if the corresponding human leukocyte antigen complex (HLA) also influences susceptibility to pain, we performed an association study in patients that had undergone surgery for inguinal hernia (n=189). One group had developed a chronic pain state following the surgical procedure, while the control group had undergone the same type of operation, without any persistent pain. HLA DRB1genotyping revealed a significantly increased proportion of patients in the pain group carrying DRB1*04 compared to patients in the pain-free group. Additional typing of the DQB1 gene further strengthened the association; carriers of the DQB1*03:02 allele together with DRB1*04 displayed an increased risk of postsurgery pain with an odds risk of 3.16 (1.61-6.22) compared to noncarriers. This finding was subsequently replicated in the clinical material of patients with lumbar disc herniation (n=258), where carriers of the DQB1*03:02 allele displayed a slower recovery and increased pain. In conclusion, we here for the first time demonstrate that there is an HLA-dependent risk of developing pain after surgery or lumbar disc herniation; mediated by the DRB1*04 - DQB1*03:02 haplotype. Further experimental and clinical studies are needed to fine-map the HLA effect and to address underlying mechanisms.

Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons.

Long-term potentiation (LTP), a use dependent long-lasting modification of synaptic strength, was first discovered in the hippocampus and later shown to occur in sensory areas of the spinal cord. Here we demonstrate that spinal LTP requires the activation of a subset of superficial spinal dorsal horn neurons expressing the neurokinin-1 receptor (NK1-R) that have previously been shown to mediate certain forms of hyperalgesia. These neurons participate in local spinal sensory processing, but are also the origin of a spino-bulbo-spinal loop driving a 5-hydroxytryptamine 3 receptor (5HT3-R)- mediated descending facilitation of spinal pain processing. Using a saporin-substance P conjugate to produce site-specific neuronal ablation, we demonstrate that NK1-R expressing cells in the superficial dorsal horn are crucial for the generation of LTP-like changes in neuronal excitability in deep dorsal horn neurons and this is modulated by descending 5HT3-R-mediated facilitatory controls. Hippocampal LTP is associated with early expression of the immediate-early gene zif268 and knockout of the gene leads to deficits in long-term LTP and learning and memory. We found that spinal LTP is also correlated with increased neuronal expression of zif268 in the superficial dorsal horn and that zif268 antisense treatment resulted in deficits in the long-term maintenance of inflammatory hyperalgesia. Our results support the suggestion that the generation of LTP in dorsal horn neurons following peripheral injury may be one mechanism whereby acute pain can be transformed into a long-term pain state.

Cellular memory in spinal nociceptive circuitry.

Besides transmitting and processing, neurons may also store information for prolonged periods of time (e.g. by use-dependent change in synaptic strength). In 1966 long-term potentiation (LTP) of synaptic transmission was discovered in the hippocampus, an area implicated in learning and memory. Recent studies show that similar mechanisms apply to pain pathways, at least in the spinal cord, and may account for some forms of clinical problems like hyperalgesia, allodynia, and deafferentation pain states, such as phantom pain. In this review, we briefly summarize key aspects of synaptic plasticity known from the brain and in the spinal cord. Then we describe and discuss related changes in spinal nociceptive neurons based on results from our own laboratory.