Sublingual buprenorphine versus intravenous or intramuscular morphine in acute pain: A systematic review and meta-analysis of randomized control trials

Intro

Buprenorphine is a potent analgesic agent with several unique and favourable features such as its sublingual formulation. The aim of this study is to compare the effectiveness of sublingual versus intramuscular and intravenous buprenorphine in acute pain.

Fulminant hepatic failure after intravenous injection of sublingual buprenorphine in a patient with hepatitis C

A 20‐year‐old indigenous Australian male was admitted to the intensive care unit with fulminant hepatic failure secondary to intravenous use of buprenorphine, which had been prescribed sublingually for opioid dependence. Intravenous buprenorphine‐induced hepatitis is well recognized, however, life‐threatening fulminant hepatic failure has not previously been reported.     

Treatment of cancer-related pain with transdermal buprenorphine: a report of three cases

Three patients suffering from pain arising from renal and metastasing prostate and breast cancer were successfully treated with transdermal buprenorphine. The three cases demonstrate that transdermal buprenorphine is an easy-to-use and effective therapeutic option for the treatment of advanced cancer pain, that it can also be used in opioid rotation as an alternative after formerly applied steps II or III opioids have failed and that long-term treatment without dose escalation or compromise in tolerability is possible.     

Brain dynamics for perception of tactile allodynia (touch-induced pain) in postherpetic neuralgia

Postherpetic neuralgia (PHN) is a debilitating chronic pain condition often accompanied by a sensation of pain when the affected region is touched (tactile allodynia). Here we identify brain regions involved in stimulus-induced touch-evoked pain (dynamical mechanical allodynia, DMA), compare brain activity between DMA and spontaneous pain (described earlier for the same patients in [Geha PY, Baliki MN, Chialvo DR, Harden RN, Paice JA, Apkarian AV. Brain activity for spontaneous pain of postherpetic neuralgia and its modulation by lidocaine patch therapy. Pain 2007;128:88-100]), delineate regions that specifically code the magnitude of perceived allodynia, and show the transformation of allodynia-related information in the brain as a time-evolving network. Eleven PHN patients were studied for DMA and its modulation with Lidoderm therapy (patches of 5% lidocaine applied to the PHN affected body part). Continuous ratings of pain while the affected body part was brushed during fMRI were contrasted with non-painful touch when brushing was applied to an equivalent opposite body site, and with fluctuations of a bar observed during scanning, at three sessions relative to Lidoderm treatment. Lidoderm treatment did not decrease DMA ratings but did decrease spontaneous pain. Multiple brain areas showed preferential activity for allodynia. However, mainly responses in the bilateral putamen and left medial temporal gyrus were related to the magnitude of allodynia. Both DMA and spontaneous pain perceptions were best represented within the same sub-cortical structures but with minimal overlap, implying that PHN pain modulates behavioral learning and hedonics. These results have important clinical implications regarding adequate therapy.     

A pilot trial of intravenous pamidronate for chronic low back pain

Intravenous (i.v.) bisphosphonates relieve pain in conditions such as Paget’s disease of bone, metastatic bone disease, and multiple myeloma. Based on positive findings from a prior case series, we conducted a randomized placebo-controlled study to assess the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine. Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180 mg pamidronate (the latter administered as two 90 mg infusions). Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6 months postinfusion using electronic diaries. Secondary outcomes included responder rate, daily worst pain, and pain-related interference with daily function. There were no pamidronate-related serious adverse events or other significant safety findings. A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6 months in the 180 mg pamidronate group. Least squares mean changes in daily average pain score were −1.39 (SE = 0.43) for placebo, and −1.53 (0.71), −1.26 (0.81), −1.42 (0.65), and −4.13 (0.65) for pamidronate 30, 60, 90, and 180 mg, respectively (P = 0.012 for pamidronate 180 mg vs placebo). The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180 mg compared with placebo. In conclusion, i.v. pamidronate, administered as two 90 mg infusions, decreased pain intensity for 6 months in subjects with CLBP.     

Safety of buprenorphine transdermal system in the management of pain in older adults

Objectives: To evaluate whether buprenorphine transdermal system (BTDS; Butrans®) is an option for the treatment of chronic pain in older adults.

Methods: This retrospective analysis of 16 placebo- and active-controlled and uncontrolled studies (N = 6566) evaluated the safety and tolerability profile in patients exposed to BTDS and compared the safety profiles associated with BTDS treatment in older patients ≥ 65 years of age (65 to 98 years) and younger patients < 65 years of age (18 to 64 years). Safety analyses included adverse events (AEs), laboratory values, and electrocardiograms.

Results: Overall, the incidence of AEs was similar in the ≥ 65 year patient cohort (N = 1715) and the < 65 year patient cohort (N = 4843) (63.8% and 61.0%, respectively). The older patient cohort experienced more constipation, peripheral edema, and urinary tract infection, but fewer application-site AEs (eg, erythema, irritation, pruritus, rash) and headaches. A statistically significant treatment-by-age interaction was observed for fall, arthralgia, and localized and non-application site-related rash, suggesting a differential increase in the risk of these events among older patients treated with BTDS that cannot be explained by age or treatment alone. A similar trend was observed for accidents and injuries, and for falls, in patients treated with both BTDS and active controls (oxycodone/acetaminophen [OXY/APAP] and hydrocodone/acetaminophen [HCD/APAP]), suggesting an opioid class effect. However, due to small sample sizes of the active control groups, a statistical test of treatment-by-age interaction could not be conducted for the active controls. The incidences of serious AEs and of clinically significant increases in liver enzymes, such as AST, ALT and bilirubin were small, regardless of age.

Conclusion: BTDS appears to be a viable option for the management of pain in older adults, but the benefits need to be tempered by potential risks among older adults.     

The contribution of sensory system functional connectivity reduction to clinical pain in fibromyalgia

Fibromyalgia typically presents with spontaneous body pain with no apparent cause and is considered pathophysiologically to be a functional disorder of somatosensory processing. We have investigated potential associations between the degree of self-reported clinical pain and resting-state brain functional connectivity at different levels of putative somatosensory integration. Resting-state functional magnetic resonance imaging was obtained in 40 women with fibromyalgia and 36 control subjects. A combination of functional connectivity-based measurements were used to assess (1) the basic pain signal modulation system at the level of the periaqueductal gray (PAG); (2) the sensory cortex with an emphasis on the parietal operculum/secondary somatosensory cortex (SII); and (3) the connectivity of these regions with the self-referential “default mode” network. Compared with control subjects, a reduction of functional connectivity was identified across the 3 levels of neural processing, each showing a significant and complementary correlation with the degree of clinical pain. Specifically, self-reported pain in fibromyalgia patients correlated with (1) reduced connectivity between PAG and anterior insula; (2) reduced connectivity between SII and primary somatosensory, visual, and auditory cortices; and (3) increased connectivity between SII and the default mode network. The results confirm previous research demonstrating abnormal functional connectivity in fibromyalgia and show that alterations at different levels of sensory processing may contribute to account for clinical pain. Importantly, reduced functional connectivity extended beyond the somatosensory domain and implicated visual and auditory sensory modalities. Overall, this study suggests that a general weakening of sensory integration underlies clinical pain in fibromyalgia.     

The effect of venlafaxine on ongoing and experimentally induced pain in neuropathic pain patients: a double blind, placebo controlled study.

BACKGROUND AND AIM: The aim of this randomized double blind placebo controlled study was to investigate the effectiveness and the safety of venlafaxine XR 75 and 150 mg on ongoing pain and on quantitative sensory tests in 60 patients with neuropathic pain for 8 weeks. METHODS: Evaluation parameters consisted of ongoing pain intensity (VAS), patient satisfaction, side effects, global efficacy and tolerance. Quantitative sensory measurements taken from the affected area before and after the drug treatment included pin-prick hyperalgesia, allodynia, detection and pain thresholds to electrical and heat stimuli, temporal summation of repetitive electrical and heat stimuli. RESULTS: A total of 55 patients completed the study. VAS scores decreased significantly compared to the baseline measurements in all groups. There was no significant difference between the groups regarding pain intensity and escape medication. The areas of allodynia and pin-prick hyperalgesia decreased significantly in venlafaxine groups compared to the placebo. There was no significant difference between the groups regarding the detection thresholds (electrical and heat). The pain threshold and the summation threshold to electrical stimuli and the summation threshold to heat stimuli increased significantly following treatment in both venlafaxine groups. In addition, the degree of the temporal summation to electrical and heat stimuli decreased significantly following treatment in both venlafaxine groups compared to the placebo. CONCLUSION: The study showed significant effect of venlafaxine in the manifestations of hyperalgesia and temporal summation, but not on the ongoing pain intensity. Furthermore, the quantitative sensory tests provided complementing information to the clinical measures.     

慢性疼痛静息态脑功能连接研究的Meta分析

目的用Meta分析方法系统地描绘慢性疼痛患者静息态脑功能连接的变化特点。材料与方法数据库检索Pubmed、EMBASE、Web Science、Science Direct、Springerlink、brainmap自建库至2016年9月符合纳入标准的所有f MRI研究。利用Icbm2tal软件将Talairach坐标统一转换为MNI坐标,依据ALE手册中数据录入方法将坐标数据分组录入,使用Ginger-ALE 2.3软件进行Meta分析并计算脑区ALE分布图。结果纳入20篇文献,共389名慢性疼痛患者。Meta分析结果表明,慢性疼痛会导致默认网络的功能连接出现异常。选取岛叶作为种子点,研究发现:岛叶和楔前叶;岛叶和前扣带回;岛叶和后扣带回;岛叶和顶下小叶;岛叶和内侧前额叶的功能连接均出现异常。结论静息态下慢性疼痛患者的岛叶与默认网络的功能连接异常,反映出疼痛脑加工与感知觉辨认、认知和情绪相关脑区活动有关,为慢性疼痛下的神经认知模型提供了实证基础,有助于进一步探索疼痛与脑之间的联系。     

Exploring the brain in pain: Activations,deactivations and their relation

The majority of neuroimaging studies on pain focuses on the study of BOLD activations, and more rarely on deactivations. In this study, in a relatively large cohort of subjects (N = 61), we assess (a) the extent of brain activation and deactivation during the application of two different heat pain levels (HIGH and LOW) and (b) the relations between these two directions of fMRI signal change. Furthermore, in a subset of our subjects (N = 12), we assess (c) the functional connectivity of pain-activated or -deactivated regions during resting states. As previously observed, we find that pain stimuli induce intensity dependent (HIGH pain > LOW pain) fMRI signal increases across the pain matrix. Simultaneously, the noxious stimuli induce activity decreases in several brain regions, including some of the ‘core structures’ of the default network (DMN). In contrast to what we observe with the signal increases, the extent of deactivations is greater for LOW than HIGH pain stimuli. The functional dissociation between activated and deactivated networks is further supported by correlational and functional connectivity analyses. Our results illustrate the absence of a linear relationship between pain activations and deactivations, and therefore suggest that these brain signal changes underlie different aspects of the pain experience.     

The impact of Alzheimer's disease on the functional connectivity between brain regions underlying pain perception

Patients with Alzheimer's disease (AD) are administered fewer analgesics and report less clinical pain compared with their cognitively‐intact peers, prompting much speculation about the likely impact of neurodegeneration on pain perception and processing. This study used functional connectivity analysis to examine the impact of AD on the integrated functioning of brain regions mediating the sensory, emotional, and cognitive aspects of pain. Fourteen patients with AD and 15 controls attended two experimental sessions. In an initial psychophysical testing session, a random staircase procedure was used to assess sensitivity to noxious mechanical pressure applied to the thumbnail. In a subsequent brain imaging session, fMRI data were collected as participants received noxious or innocuous thumbnail pressure, delivered at intensities corresponding with previously identified subjective pain thresholds. Two approaches to functional connectivity analysis were utilised. A seed‐based correlation method was first used to identify regions showing significant functional connectivity with the right dorsolateral prefrontal cortex (DLPFC). Functional connectivity between a network of 17 predefined pain processing regions was then assessed. Between‐group comparisons revealed enhanced functional connectivity between the DLPFC and the anterior mid cingulate cortex, periaqueductal grey, thalamus, hypothalamus, and several motor areas in patients with AD compared with control group. Likewise, inter‐regional functional connectivity across most regions of the predefined pain network was shown to be greater in the patient group, with the enhanced functional connectivity centred on three nodes: the DLPFC‐R, hypothalamus, and PAG. The results of this study support previous research suggesting an interplay between pain and cognitive processes in patients with AD.     

Functional connectivity mapping of the human precuneus by resting state fMRI

Precuneus responds to a wide range of cognitive processes. Here, we examined how the patterns of resting state connectivity may define functional subregions in the precuneus. Using a K-means algorithm to cluster the whole-brain “correlograms” of the precuneus in 225 adult individuals, we corroborated the dorsal-anterior, dorsal-posterior, and ventral subregions, each involved in spatially guided behaviors, mental imagery, and episodic memory as well as self-related processing, with the ventral precuneus being part of the default mode network, as described extensively in earlier work. Furthermore, we showed that the lateral/medial volumes of dorsal anterior and dorsal posterior precuneus are each connected with areas of motor execution/attention and motor/visual imagery, respectively. Compared to the ventral precuneus, the dorsal precuneus showed greater connectivity with occipital and posterior parietal cortices, but less connectivity with the medial superior frontal and orbitofrontal gyri, anterior cingulate cortex as well as the parahippocampus. Compared to dorsal-posterior and ventral precuneus, the dorsal-anterior precuneus showed greater connectivity with the somatomotor cortex, as well as the insula, supramarginal, Heschl's, and superior temporal gyri, but less connectivity with the angular gyrus. Compared to ventral and dorsal-anterior precuneus, dorsal-posterior precuneus showed greater connectivity with the middle frontal gyrus. Notably, the precuneus as a whole has negative connectivity with the amygdala and the lateral and inferior orbital frontal gyri. Finally, men and women differed in the connectivity of precuneus. Men and women each showed greater connectivity with the dorsal precuneus in the cuneus and medial thalamus, respectively. Women also showed greater connectivity with ventral precuneus in the hippocampus/parahippocampus, middle/anterior cingulate gyrus, and middle occipital gyrus, compared to men. Taken together, these new findings may provide a useful platform upon which to further investigate sex-specific functional neuroanatomy of the precuneus and to elucidate the pathology of many neurological illnesses.     

Functional connectivity of the frontoparietal network predicts cognitive modulation of pain

The experience of pain can be significantly influenced by expectancy (predictive cues). This ability to modulate pain has the potential to affect therapeutic analgesia substantially and constitutes a foundation for nonpharmacological pain relief. In this study, we investigated (1) brain regions involved in visual cue modulation of pain during anticipation of pain, pain administration, and pain rating; and (2) the association between pretest resting state functional connectivity and the magnitude of cue effects on pain ratings. We found that after cue conditioning, visual cues can significantly modulate subjective pain ratings. Functional magnetic resonance imaging results suggested that brain regions pertaining to the frontoparietal network (prefrontal and parietal cortex) and a pain/emotion modulatory region (rostral anterior cingulate cortex) are involved in cue modulation during both pain anticipation and administration stage. Most interestingly, we found that pretest resting state functional connectivity between the frontoparietal network (as identified by independent component analysis) and the rostral anterior cingulate cortex/medial prefrontal cortex was positively associated with cue effects on pain rating changes. We believe that these findings will shed new light on our understanding of variable cue/expectancy effects across individuals and how the intrinsic connectivity of the brain may influence expectancy-induced modulation of pain.     

Attenuation of experimental pain by vibro-tactile stimulation in patients with chronic local or widespread musculoskeletal pain

Patients with chronic pain syndromes, like fibromyalgia (FM) complain of widespread pain and tenderness, as well as non-refreshing sleep, cognitive dysfunction, and negative mood. Several lines of evidence implicate abnormalities of central pain processing as contributors for chronic pain, including dysfunctional descending pain inhibition. One form of endogenous pain inhibition, diffuse noxious inhibitory controls (DNIC), has been found to be abnormal in some chronic pain patients and evidence exists for deficient spatial summation of pain, specifically in FM. Similar findings have been reported in patients with localized musculoskeletal pain (LMP) disorders, like neck and back pain. Whereas DNIC reduces pain through activation of nociceptive afferents, vibro-tactile pain inhibition involves innocuous A-beta fiber. To assess whether patients with localized or widespread chronic pain disorders have dysfunctional A-beta related pain inhibition we enrolled 28 normal pain-free controls (NC), 29 FM patients, and 19 subjects with neck or back pain. All received 10 s sensitivity-adjusted noxious heat stimuli to the forearms as test stimuli. To assess endogenous analgesic mechanisms of study subjects, vibro-tactile conditioning stimuli were simultaneously applied with test stimuli either homotopically or heterotopically. Additionally, the effect of distraction on experimental pain was assessed. Homotopic vibro-tactile stimulation resulted in 40% heat pain reductions in all subject groups. Distraction did not seem to affect experimental pain ratings. Conclusions: Vibro-tactile stimulation effectively recruited analgesic mechanisms not only in NC but also in patients with chronic musculoskeletal pain, including FM. Distraction did not seem to contribute to this analgesic effect.     

神经外科开颅术后患者疼痛及控制状况的调查

目的调查神经外科开颅手术患者术后疼痛及控制状况,为术后镇痛治疗提供依据。方法选择北京天坛医院神经外科开颅手术患者100例,采用疼痛视觉模拟评分（VAS）、Ramsay镇静评分于术后2h和24h评估患者意识和疼痛状况,并进行术后疼痛调查问卷,记录不良事件。结果本组患者术后均使用静脉镇痛泵。术后2h无痛38例（38％）,轻度疼痛49例（49％）,中度疼痛12例（12％）,重度疼痛1例（1％）;术后24h无痛24例（24％）,轻度疼痛30例（30％）,中度疼痛36例（36％）,重度疼痛10例（10％）。结论神经外科开颅手术患者术后存在不同程度的疼痛,术后镇痛需要进一步深化。     

TE-dependent spatial and spectral specificity of functional connectivity

Previous studies suggest that spontaneous fluctuations in the resting-state fMRI (RS-fMRI) signal may reflect fluctuations in transverse relaxation time (T₂^?) rather than spin density (S₀). However, such S₀ and T₂^? features have not been well characterized. In this study, spatial and spectral characteristics of functional connectivity on sensorimotor, default-mode, dorsal attention, and primary visual systems were examined using a multiple gradient-echo sequence at 3 T. In the spatial domain, we found broad, local correlations at short echo times (TE ≤ 14 ms) due to dominant S₀ contribution, whereas long-range connections mediated by T₂^? became explicit at TEs longer than 22 ms. In the frequency domain, compared with the flat spectrum of S₀, spectral power of the T₂^?-weighted signal elevated significantly with increasing TE, particularly in the frequency ranges of 0.008-0.023 Hz and 0.037-0.043 Hz. Using the S₀ spectrum as a reference, we propose two indices to measure spectral signal change (SSC) and spectral contrast-to-noise ratio (SCNR), respectively, for quantifying the RS-fMRI signal. These indices demonstrated TE dependency of connectivity-related fluctuation strength, resembling functional contrasts in activation-based fMRI. These findings further confirm that large-scale functional circuit connectivity based on BOLD contrast may be constrained within specific frequency ranges in every brain network, and the spectral features of S₀ and T₂^? could be valuable for interpreting and quantifying RS-fMRI data.     

Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine

The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with end-stage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R=0.74; P<0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 microg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.