Cryoneurolysis in Patients with Dorsal Neuropathic Pain Secondary to Tumor Invasion.

PURPOSE: To evaluate the safety and efficacy of cryoneurolysis (CNL) in patients with refractory thoracic neuropathic pain related to tumor invasion. MATERIALS AND METHODS: Between January 2013 and May 2017, this single-center and retrospective study reviewed 27 computed tomography-guided CNLs performed on 26 patients for refractory thoracic neuropathic pain related to tumor invasion. Patients with cognitive impairment were excluded. Pain levels were recorded on a visual analog scale (VAS) before the procedure, on days 1, 7, 14, 28 and at each subsequent follow-up appointment. CNL was clinically successful if the postprocedural VAS decreased by 3 points or more. To determine the duration of clinical success, the end of pain relief was defined as either an increased VAS of 2 or more points, the introduction of a new analgesic treatment, a death with controlled pain, or for lost to follow-up patients, the latest follow-up appointment date with controlled pain. RESULTS: Technical success rate was 96.7% and clinical success rate was 100%. Mean preprocedural pain score was 6.4 ± 1.7 and decreased to 2.4 ± 2.4 at day 1; 1.8 ± 1.7 at day 7 (P < .001); 3.3 ± 2.5 at day 14; 3.4 ± 2.6 at day 28 (P < .05). The median duration of pain relief was 45 days (range 14-70). Two minor complications occurred. CONCLUSIONS: Cryoneurolysis is a safe procedure that significantly decreased pain scores in patients with thoracic neuropathic pain related to tumor invasion, with a median duration of clinical success of 45 days.

Measuring sensory and pain thresholds by Semmes-Weinstein monofilaments in patients with leg ulcers: a pilot study.

OBJECTIVE: Pain is a common and disabling symptom in patients with leg ulcers. Clinical quantification of pain mostly depends on subjective pain reports, which do not reveal underlying mechanisms. The aim of this pilot study is to identify mechanisms underlying the pain in patients with leg ulcers by documenting alterations in pain processing using quantitative sensory testing. METHODS: In nine ulcer patients the mechanical sensory thresholds and the mechanical pain thresholds were determined by Semmes-Weinstein monofilaments (SWM) at three different sites: on the contralateral (unaffected) leg, on the skin of the affected leg 10cm from the ulcer margin, and on the affected leg, close (1-2cm) to the ulcer margin. Besides the mechanical sensory thresholds and mechanical pain thresholds, pain at the site of the ulcer, using an 11-point numeric rating scale (NRS), was documented. RESULTS: Mechanical sensory thresholds were increased in all subjects. Almost half (44%) of patients consistently showed allodynia at the unaffected site. The lowering of mechanical pain thresholds correlated with higher scores on the NRS. CONCLUSION: All patients showed diminished touch and/or protective sensation, which might have contributed to ulcer development via (partial) loss of protective function. The allodynia at the unaffected site suggests the presence of central sensitisation of pain processing.

Defining refractory rheumatoid arthritis.

While biologic disease-modifying antirheumatic drugs (bDMARDs) have transformed outcomes of people with rheumatoid arthritis (RA), a proportion of patients are refractory to multiple bDMARDs. Definitions of refractory RA thus far have been arbitrary, and outcome data and impact of such cohorts remain limited. Extrapolation from randomised controlled trial and some real-life data suggest approximately 20% progress onto a third bDMARD with a more modest proportion failing additional bDMARDs. This viewpoint discusses an opinion of refractory RA disease and proposes key principles to accurately identify refractory cohorts. These include demonstrating presence of persistent inflammation despite multiple therapies and acknowledging development of antidrug antibody. Potential basis of refractory disease is summarised, and suggestions for an initial approach in the future evaluation of refractory disease are offered. Specific investigation of refractory RA disease is necessary to inform the clinical need and provide a basis for robust investigation of underlying mechanisms.

New insights into perineural invasion of pancreatic cancer: More than pain.

Pancreatic cancer is one of the most malignant human tumors. Perineural invasion, whereby a cancer cell invades the perineural spaces surrounding nerves, is acknowledged as a gradual contributor to cancer aggressiveness. Furthermore, perineural invasion is considered one of the root causes of the recurrence and metastasis observed after pancreatic resection, and it is also an independent predictor of prognosis. Advanced research has demonstrated that the neural microenvironment is closely associated with perineural invasion in pancreatic cancer. Therapy targeting the molecular mechanism of perineural invasion may enable the durable clinical treatment of this formidable disease. This review provides an overview of the present status of perineural invasion, the relevant molecular mechanisms of perineural invasion, pain and hyperglycemia associated with perineural invasion in pancreatic cancer, and the targeted therapeutics based on these studies.

Efficacy and safety of fulranumab as monotherapy in patients with moderate to severe, chronic knee pain of primary osteoarthritis: a randomised, placebo- and active-controlled trial.

AIMS: The efficacy and safety of monotherapy with fulranumab, a monoclonal antibody that neutralises human nerve growth factor (NGF), was evaluated compared with placebo and an active comparator, controlled-release (CR) oxycodone, in patients with moderate to severe chronic knee pain of primary osteoarthritis (OA). METHODS: In this phase-2, double-blind (DB), double-dummy, placebo- and active-controlled study, patients (40-80 years) were randomised (1:1:1:1) to placebo, fulranumab 3 or 9mg every 4 weeks (Q4 wk), or oxycodone CR twice-daily. Primary efficacy end-point: responder rates based on percent improvement in average osteoarthritis-related pain intensity (OAPI) scores from baseline to week-12 or when Food and Drug Administration (FDA) put a clinical hold on all anti-NGF trials, whichever was earlier. Secondary efficacy end-points: average OAPI score (week-16), Western Ontario and McMaster Osteoarthritis Index Global Score and subscales (pain, physical function, stiffness), and Patient Global Assessment. RESULTS: As of an FDA clinical hold on all anti-NGF trials, only 196/300 patients were randomised and 33% (65/196) had completed 12 weeks of the 16-week DB phase. Responders were patients who did not withdraw and whose pain improved. Responder rates were not significantly different between fulranumab treatment groups (3mgQ4wk: 71%, p = 0.739; 9mgQ4wk: 80%, p = 0.843) and placebo (77%), whereas, oxycodone CR (56%) had significantly lower responder rates in comparison to both fulranumab (3mgQ4wk: p = 0.008; 9mgQ4wk: p = 0.012) and placebo (p = 0.0021). Secondary efficacy results were consistent with primary. None of the joint replacements (four in three patients) were adjudicated as rapidly progressing OA/osteonecrosis. CONCLUSION: Low sample size because of early termination make interpretation of this study difficult, but fulranumab monotherapy resulted in significantly better pain relief and function compared with oxycodone CR (but not against placebo) and was generally well-tolerated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01094262.

Inducible Lentivirus-Mediated siRNA against TLR4 Reduces Nociception in a Rat Model of Bone Cancer Pain.

Although bone cancer pain is still not fully understood by scientists and clinicians alike, studies suggest that toll like receptor 4 (TLR4) plays an important role in the initiation and/or maintenance of pathological pain state in bone cancer pain. A promising treatment for bone cancer pain is the downregulation of TLR4 by RNA interference; however, naked siRNA (small interference RNA) is not effective in long-term treatments. In order to concoct a viable prolonged treatment for bone cancer pain, an inducible lentivirus LvOn-siTLR4 (tetracycline inducible lentivirus carrying siRNA targeting TLR4) was prepared and the antinociception effects were observed in bone cancer pain rats induced by Walker 256 cells injection in left leg. Results showed that LvOn-siTLR4 intrathecal injection with doxycycline (Dox) oral administration effectively reduced the nociception induced by Walker 256 cells while inhibiting the mRNA and protein expression of TLR4. Proinflammatory cytokines as TNF-α and IL-1ß in spinal cord were also decreased. These findings suggest that TLR4 could be a target for bone cancer pain treatment and tetracycline inducible lentivirus LvOn-siTLR4 represents a new potential option for long-term treatment of bone cancer pain.

Breakthrough pain in cancer patients: prevalence, mechanisms and treatment options.

PURPOSE OF REVIEW: The aim of this article was to examine the definition, the characteristics, and the management of breakthrough cancer pain (BTP) in cancer patients by a critical review of recent literature. RECENT FINDINGS: BTP should be more correctly defined as an episode of severe intensity in patients receiving an adequate treatment with opioids able to provide at least mild analgesia. BTP is a heterogeneous condition as episodes vary between individuals. BTP can be classified into two big distinct pictures: spontaneous-type and incident-type pain. The principal pharmacological treatment of BTP is represented by the administration of opioids as needed. Recent reviews revealed that transmucosal preparation of fentanyl provided superior and more rapid pain relief as compared with placebo in the first 30 min after dosing. Few comparison studies among fentanyl products have been performed.Finally, although dose titration was recommended for years, a meaningful dosing according to the level of opioid tolerance may enhance the advantages of such products. SUMMARY: BTP represents a serious problem reported by many cancer patients despite receiving regular use of opioids. Subgroups of breakthrough pain have been identified. Different modalities of pharmacological interventions are available. Further studies are warranted to assess the net benefit of these drugs to assist decision-making by patients, clinicians, and payers according to individual clinical conditions.

Do low levels of beta-endorphin in the cerebrospinal fluid indicate defective top-down inhibition in patients with chronic neuropathic pain? A cross-sectional, comparative study.

OBJECTIVE: Pain medicine still lacks mechanism-specific biomarkers to guide diagnosis and treatment, and defective top-down modulation is an important factor in the pathophysiology of chronic pain conditions. Using modern analytical tools and advanced multivariate statistical analysis, the aim of this study was to revisit two classical potential biomarkers of pro- and anti-nociception in humans (substance P and beta-endorphin), focusing particularly on the cerebrospinal fluid (CSF). DESIGN: Cross-sectional, comparative, observational study. SUBJECTS: Patients with chronic, post-traumatic and/or post-surgical, neuropathic pain refractory to conventional treatment (N = 15) and healthy controls (N = 19) were included. METHODS: Samples were taken from CSF and blood, and levels of substance P and beta-endorphin were investigated using a Luminex technology kit. RESULTS: We found low levels of beta-endorphin in the CSF of neuropathic pain patients (66 ± 11 pcg/mL) compared with healthy controls (115 ± 14 pcg/mL) (P = 0.017). Substance P levels in the CSF did not differ (20 ± 2 pcg/mL, 26 ± 2, P = 0.08). However, our multivariate data analysis showed that belonging to the patient group was associated with low levels of both substances in the CSF. A higher correlation between the levels of beta-endorphin and substance P in CSF was found in healthy controls than in patients (rs = 0.725, P < 0.001 vs. rs = 0.574, P = 0.032). CONCLUSIONS: Patients with chronic neuropathic pain due to trauma or surgery had low levels of beta-endorphin in the CSF. We speculate that this could indicate a defective top-down modulation of pain in chronic neuropathic pain. Our results also illustrate the importance of taking a system-wide, multivariate approach when searching for biomarkers.

Deep brain and motor cortex stimulation.

Deep brain stimulation (DBS) and motor cortex stimulation (MCS) are established surgical modalities that have been successfully used over the last several decades for treatment of numerous chronic pain disorders. Most often, these approaches are reserved for severe, disabling, and medically refractory syndromes after less invasive approaches have been tried and have failed. Although the exact mechanism of action for DBS and MCS remains unknown, it appears that these central neuromodulation processes have multifactorial effects on central pain processing and descending pain inhibition. Clinical studies and laboratory reports have shed some light on stimulation details and optimal parameters, as well as the choice of stimulation targets, best surgical indications, and expected long-term outcomes. Based on the worldwide published experience, it appears that additional data is needed to obtain regulatory approval for both MCS and DBS for the treatment of pain. Following approval, further clinical research will shape the ability to initiate, implement, and update comprehensive patient and procedure selection paradigms.

Considerations for evaluating the use of intrathecal drug delivery in the oncologic patient.

While the majority of cancer pain patients are successfully managed with conservative medical management, some patients may suffer from intractable pain or intolerable side effects. The implantation of an intrathecal drug delivery system offers many advantages to improve both analgesia and side effect profile. Practitioners may decide to proceed toward implantation after appropriate patient selection, and, when applicable, a suitable trial for the device. Once implantation is completed, multiple medication combinations may be used to optimize the therapeutic benefit of the device. We describe a stepwise paradigm to implement an intrathecal drug delivery program in the cancer pain population.

Spinal cord stimulation for intractable chronic pain.

Spinal cord stimulation (SCS) is minimally invasive and reversible therapy for treatment of severe, otherwise nonresponsive chronic pain. Such approach is relatively safe, with very few side-effects, not addictive, and provides enduring therapeutic response. A number of clinical studies support the efficacy of spinal cord stimulation in treating failed back surgery syndrome and complex regional pain syndrome, as well as peripheral neuropathic pain, postamputation pain, postherpetic neuralgia, root and spinal cord injury pain. In addition, neurostimulation has been used to treat refractory angina, chronic abdominal pain, peripheral vascular disease, and vaso-occlusive syndromes. Clinical use of spinal cord stimulation is expanding at very fast pace, and new technological modalities in SCS will provide a new clinical evidence with likely better pain control.

Intrathecal therapy for chronic pain: current trends and future needs.

The management of chronic pain continues to pose many challenges to healthcare providers. Intrathecal drug delivery systems (IDDS) provide an effective therapy for patients suffering from chronic pain intractable to medical management. However, the clinical growth of intrathecal therapy continues to face many challenges, and is likely underutilized secondary to its high-complexity and limited reimbursement. The clinical utility of IDDS remains limited by lack of prospective randomized, placebo-controlled studies. In addition, there remains a need to enhance physician knowledge on the pharmacodynamics and pharmacokinetics of intrathecal drug delivery and promote further research into this field and drug delivery modalities. The purpose of this article is to provide a comprehensive review of the determinants of successful intrathecal drug delivery with an emphasis on its use in noncancer pain.

Managing difficult pain conditions in the cancer patient.

Whereas most pain due to cancer can be relieved with relatively simple methods using oral analgesics, as suggested by WHO guidelines, some patients may have difficult pain situations that require more complex approaches. It is estimated that 10-20 % of cancer patients suffer from pain that is not easily relieved. There are a number of factors that may reduce the efficacy of opioids in the management of cancer pain. Neuropathic pain (NP) and breakthrough pain (BP), especially of the incident subtype, have been identified as challenges for clinicians. In several prognostic studies, these two mechanisms were associated with limited positive outcomes compared with other syndromes. Opioid-induced hyperalgesia has recently been described as representing a challenge for physicians in the clinical setting. The global response to opioids, including the development of adverse effects, typically varies by individual and is likely genetically determined. Moreover, clinical evidence suggests that different opioids may produce different effect profiles, and so it is more appropriate to consider the response to each individual opioid rather than general opioid response. This paper will review both pharmacological and procedural mechanisms and treatments of these difficult pain syndromes.

T-type calcium channels: functional regulation and implication in pain signaling.

Low-voltage-activated T-type Ca(2+) channels (T-channels), especially Cav3.2 among the three isoforms (Cav3.1, Cav3.2, and Cav3.3), are now considered to play pivotal roles in processing of pain signals. Cav3.2 T-channels are functionally modulated by extracellular substances such as hydrogen sulfide and ascorbic acid, by intracellular signaling molecules including protein kinases, and by glycosylation. Cav3.2 T-channels are abundantly expressed in both peripheral and central endings of the primary afferent neurons, regulating neuronal excitability and release of excitatory neurotransmitters such as substance P and glutamate, respectively. Functional upregulation of Cav3.2 T-channels is involved in the pathophysiology of inflammatory, neuropathic, and visceral pain. Thus, Cav3.2 T-channels are considered to serve as novel targets for development of drugs for treatment of intractable pain resistant to currently available analgesics.

Principles of electrical stimulation and dorsal column mapping as it relates to spinal cord stimulation: an overview.

The last 30 years have witnessed the growth of spinal cord stimulation as a treatment modality for an increasing number of chronic pain conditions. In spite of this growth, one of the greatest criticisms is the lack of concrete evidence for the mechanism of action. With the ever increasing enlightenment with regards to the neurophysiology of pain, and the development of more dynamic neuroimaging techniques, the opportunity to better define the mechanism of action of the spinal cord stimulator will continue to expand. In the interim, clinicians will benefit from the consolidation of the available knowledge that will enhance the effective use of the device. This review serves to provide an overview of the key principles of electrical stimulation and dorsal column mapping as it relates to spinal cord stimulation. We aim at enhancing the understanding regarding the basis for successful placement of leads and manipulation of electrical parameters.

Surgical/radiological interventions for cancer pain.

Pain is a major morbidity associated with cancer and up to 20% patients require invasive procedures for pain relief. Ablative techniques can be directed towards the spinal cord and brain to palliate pain or modify its perception. Anterolateral cordotomy, myelotomy, DREZotomy and cingulotomy are useful interventions for the management of refractory cancer pain. Advanced imaging modalities, including intraoperative computed tomography (CT) guidance, have increased safety and efficacy of these interventions. In this paper, authors review the recent literature regarding surgical interventions for the management of cancer pain.

Celiac plexus block and neurolysis for pancreatic cancer.

Neurolytic celiac plexus blocks (NCPB) have been performed for many years for the treatment of cancer and some non-cancer pain conditions associated with the upper gastrointestinal tract. The block can provide adequate pain relief from the area of the distal esophagus to the transverse colon, and can be approached from a variety of ways. This is a review of the anatomy, patient selection, technique, medications used, possible complications, and efficacy of the treatment.

[Glial cells and chronic pain: from the laboratory to clinical hope]. / Cellules gliales et douleur chronique: du laboratoire a l'espoir clinique.

Despite their high prevalence, associated disability and seemingly rich pharmacopeia, the various forms of chronic pain remain frequently intractable. The past decade witnessed the rise of a concept stating that non-neuronal cells of the central nervous system, astrocytes and microglia, are crucial elements in pathological pain. This review gathers and summarizes the experimental data underpinning this theory in animal models and addresses their pertinence in humans. The potential opportunities and constraints of glial inhibition are exposed and compared to more moderate strategies of selective modulation. This therapeutic hope is particularly highlighted in our discussion of the first completed clinical trials employing glial inhibitors in the treatment of chronic pain.

Neural correlates of an injury-free model of central sensitization induced by opioid withdrawal in humans.

Preclinical evidence suggests that opioid withdrawal induces central sensitization (CS) that is maintained by supraspinal contributions from the descending pain modulatory system (DPMS). Here, in healthy human subjects we use functional magnetic resonance imaging to study the supraspinal activity during the withdrawal period of the opioid remifentanil. We used a crossover design and thermal stimuli on uninjured skin to demonstrate opioid withdrawal-induced hyperalgesia (OIH) without a CS-inducing peripheral stimulus. Saline was used in the control arm to account for effects of time. OIH in this injury-free model was observed in a subset of the healthy subjects (responders). Only in these subjects did opioid infusion and withdrawal induce a rise in activity in the mesencephalic-pontine reticular formation (MPRF), an area of the DPMS that has been previously shown to be involved in states of CS in humans, which became significant during the withdrawal phase compared with nonresponders. Paradoxically, this opioid withdrawal-induced rise in MPRF activity shows a significant negative correlation with the behavioral OIH score indicating a predominant inhibitory role of the MPRF in the responders. These data illustrate that in susceptible individuals central mechanisms appear to regulate the expression of OIH in humans in the absence of tissue injury, which might have relevance for functional pain syndromes where a peripheral origin for the pain is difficult to identify.

Treatment of cancer pain.

In patients with active cancer, the management of chronic pain is an essential element in a comprehensive strategy for palliative care. This strategy emphasises multidimensional assessment and the coordinated use of treatments that together mitigate suffering and provide support to the patient and family. This review describes this framework, an approach to pain assessment, and widely accepted techniques to optimise the safety and effectiveness of opioid drugs and other treatments. The advances of recent decades suggest a future that includes increased evidence-based targeting of specific analgesic interventions within an individualised plan of care that is appropriate throughout the course of illness.