A Narrative Review of Ultrasound-Guided and Landmark-based Percutaneous Cryoneurolysis for the Management of Acute and Chronic Pain.

PURPOSE OF REVIEW: Cryoneurolysis refers to the process of reversibly ablating peripheral nerves with extremely cold temperatures to provide analgesia for weeks to months. With ultrasound-guidance or landmark-based techniques, it is an effective modality for managing both acute and chronic pain. In this review, we summarize the reported literature behind its potential applications and efficacy. RECENT FINDINGS: Here, we summarize several studies (from case reports to clinical trials) describing the use of ultrasound-guided and landmark-based cryoneurolysis for acute and chronic pain. Acute pain indications included pain related to knee arthroplasty, limb amputations, mastectomies, shoulder surgery, rib fractures, and burn. Chronic pain indications included chronic knee pain (due to osteoarthritis), shoulder pain, painful neuropathies, postmastectomy pain syndrome, phantom limb pain, facial pain/headaches, foot/ankle pain, inguinal pain, and sacroiliac joint pain. For both acute and chronic pain indications, more high quality randomized controlled clinical trials are needed to definitively assess the efficacy of cryoneurolysis versus other standard therapies for a multitude of pain conditions.

Smallest Clinically Meaningful Improvement in Amputation-Related Pain and Brief Pain Inventory Scores as Defined by Patient Reports of Global Improvement After Cryoneurolysis: a Retrospective Analysis of a Randomized, Controlled Clinical Trial.

BACKGROUND: The smallest meaningful improvement in pain scores (minimal clinically important difference [MCID]) after an analgesic intervention is essential information when both interpreting published data and designing a clinical trial. However, limited information is available for patients with chronic pain conditions, and what is published is derived from studies involving pharmacologic and psychological interventions. We here calculate these values based on data collected from 144 participants of a previously published multicenter clinical trial investigating the effects of a single treatment with percutaneous cryoneurolysis. METHODS: In the original trial, we enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. At both baseline and 4 months (primary end point), participants rated their phantom limb pain based on a numeric rating scale (NRS) and their interference of pain on physical and emotional functioning as measured with the Brief Pain Inventory's interference subscale. They subsequently qualitatively defined the change using the 7-point ordinal Patient Global Impression of Change (PGIC). The smallest clinically meaningful improvements in phantom limb pain and Brief Pain Inventory scores were calculated using an anchor-based method based on the PGIC. RESULTS: The median (interquartile range [IQR]) phantom pain NRS (0-10) improvements at 4 months considered small, medium, and large were 1 [1-1], 3 [3-4], and 4 [3-6], respectively. The median improvements in the Brief Pain Inventory interference subscale (0-70) associated with a small, medium, and large analgesic changes were 16 [6-18], 24 [22-31], and 34 [22-46]. The proportions of patients that experienced PGIC ≥5 were 33% and 36% in the active and placebo groups, respectively. The relative risk of a patient experiencing PGIC ≥5 in the active group compared to the sham group with 95% confidence interval was 0.9 (0.6-1.4), P = .667. CONCLUSIONS: Amputees with phantom limb pain treated with percutaneous cryoneurolysis rate analgesic improvements as clinically meaningful similar to pharmacologic treatments, although their MCID for the Brief Pain Inventory was somewhat larger than previously published values. This information on patient-defined clinically meaningful improvements will facilitate interpretation of available studies and guide future trial design.

A Comparison of Precision and Safety using Three Recognized Ultrasound-Guided Approaches to Cervical Medial Branch Blocks: A Cadaver Study.

BACKGROUND: Ultrasound (US) guidance is widely used for needle positioning for cervical medial branch blocks (CMBB) and radiofrequency ablation, however, limited research is available comparing different approaches. OBJECTIVE: We aimed to assess the accuracy and safety of 3 different US-guided approaches for CMBB. STUDY DESIGN: A cadaveric study divided into ultrasound-guided needle placement and fluoroscopy evaluation stages. SETTING: Department of Pathology, Forensic, and Insurance Medicine, Semmelweis University. METHODS: Sonographically guided third occipital nerve (TON), C3, C4, C5 and C6 medial branch injections and radiology evaluations were performed.The 3 approaches compared were:1. ES (published by Eichenberger-Siegenthaler): US probe in the coronal plane to visualize the cervical articular pillars, needle approach out of the plane, from anterior to posterior.2. Fi (published by Finlayson): US probe in the transverse plane to visualize a cervical articular pillar and its lamina, needle approach in the plane, from posterior to anterior.3. FiM (Modified Finlayson approach): Needles are placed as in Fi, but then adjusted with a coronal view of the cervical articular pillars.Fluoroscopy images were taken and later evaluated, for "crude", "high precision" and "dangerous" placement. RESULTS: One hundred and fifty-five needle placements were assessed (10 were excluded, as no anterior-posterior fluoroscopy images were saved). Interobserver agreement on position of needle placement between the 5 observers was very high; the Fleiss' Kappa was 0.921. For crude placement, no significant differences were identified between various approaches; (77.6%, 79.5%, and 75.6% for the ES, Fi, and FiM respectively). However, for placement in predefined high-precision zones, ES resulted in significantly more success (ES: 42.9%, Fi: 22.7%, and FiM: 24.4%, P = 0.032). Fi and FiM resulted in no dangerous placements, while ES led to the potential compromise of the exiting nerve root and vertebral artery on three occasions. In 10% of the placements, the levels were identified wrongly, with no difference between the various approaches. LIMITATIONS: Feedback from a live patient, may prevent some existing nerve root injections, unlike in a cadaver. Though a higher number of needles were placed in this study than in most available publications, the number is still low at each individual medial branch level. CONCLUSION: Fi proved safer than ES. Fi was equally successful in targeting the articular pillar, however, ES proved the most successful in placing the needle in the center of the articular pillar. Adding another, (coronal) US view to check needle position in FiM did not improve safety or precision. Identifying CMB levels with the US is challenging with all approaches, therefore we still recommend using fluoroscopy for level identification. While there were pros and cons with either procedure, the efficacy findings of previous papers were not replicated on elderly cadavers with arthritic necks.

Relative Effects of Various Factors on Ice Ball Formation and Ablation Zone Size During Ultrasound-Guided Percutaneous Cryoneurolysis: A Laboratory Investigation to Inform Clinical Practice and Future Research.

INTRODUCTION: Ultrasound-guided percutaneous cryoneurolysis provides analgesia using cold temperatures to reversibly ablate peripheral nerves. Cryoneurolysis probes pass a gas through a small internal annulus, rapidly lowering the pressure and temperature, forming an ice ball to envelope the target nerve. Analgesia is compromised if a nerve is inadequately frozen, and laboratory studies suggest that pain may be paradoxically induced with a magnitude and duration in proportion with the incomplete ablation. We therefore investigated the relative effects of various factors that may contribute to the size of the ice ball and the effective cryoneurolysis zone. METHODS: A cryoprobe was inserted into a piece of meat, a gas was passed through for 2 min, and the resulting ice ball width (cross-section) and length (axis parallel to the probe) were measured using ultrasound, with the temperature evaluated in nine concentric locations concurrently. RESULTS: The factor with the greatest influence on ice ball size was probe gauge: in all probe types, a change from 18 to 14 increased ice ball width, length, and volume by up to 70%, 113%, and 512% respectively, with minimum internal temperature decreasing as much as from -5 to -32 °C. In contrast, alternating the type of meat (chicken, beef, pork) and the shape of the probe tip (straight, coudé) affected ice ball dimensions to a negligible degree. The ice ball dimensions and the zone of adequate temperature drop were not always correlated, and, even within a visualized ice ball, the temperature was often inadequate to induce Wallerian degeneration. CONCLUSIONS: Percutaneous probe design can significantly influence the effective cryoneurolysis zone; visualizing a nerve fully encompassed in an ice ball does not guarantee adequate treatment to induce the desired Wallerian degeneration because ice forms at temperatures between 0 and -20 °C, whereas only temperatures below -20 °C induce Wallerian degeneration. The correlation between temperatures in isolated pieces of meat and perfused human tissue remains unknown, and further research to evaluate these findings in situ appears highly warranted.

Ultrasound-guided Percutaneous Cryoneurolysis to Treat Chronic Postamputation Phantom Limb Pain: A Multicenter Randomized Controlled Trial.

BACKGROUND: Postamputation phantom pain is notoriously persistent with few validated treatments. Cryoneurolysis involves the application of low temperatures to reversibly ablate peripheral nerves. The authors tested the hypothesis that a single cryoneurolysis treatment would decrease phantom pain 4 months later. METHODS: The authors enrolled patients with a lower-limb amputation and established phantom pain. Each received a single-injection femoral and sciatic nerve block with lidocaine and was subsequently randomized to receive either ultrasound-guided percutaneous cryoneurolysis or sham treatment at these same locations. The primary outcome was the change in average phantom pain intensity between baseline and 4 months as measured with a numeric rating scale (0 to 10), after which an optional crossover treatment was offered. Investigators, participants, and clinical staff were masked to treatment group assignment with the exception of the treating physician performing the cryoneurolysis, who had no subsequent participant interaction. RESULTS: Pretreatment phantom pain scores were similar in both groups, with a median [quartiles] of 5.0 [4.0, 6.0] for active treatment and 5.0 [4.0, 7.0] for sham. After 4 months, pain intensity decreased by 0.5 [-0.5, 3.0] in patients given cryoneurolysis (n = 71) versus 0 [0, 3] in patients given sham (n = 73), with an estimated difference (95% CI) of -0.1 (-1.0 to 0.7), P = 0.759. Following their statistical gatekeeping protocol, the authors did not make inferences or draw conclusions on secondary endpoints. One serious adverse event occurred after a protocol deviation in which a femoral nerve cryolesion was induced just below the inguinal ligament-instead of the sensory-only saphenous nerve-which resulted in quadriceps weakness, and possibly a fall and clavicle fracture. CONCLUSIONS: Percutaneous cryoneurolysis did not decrease chronic lower extremity phantom limb pain 4 months after treatment. However, these results were based upon the authors' specific study protocol, and since the optimal cryoneurolysis treatment parameters such as freeze duration and anatomic treatment location remain unknown, further research is warranted.

A Randomized Controlled Pilot Study Using Ultrasound-Guided Percutaneous Cryoneurolysis of the Infrapatellar Branch of the Saphenous Nerve for Analgesia Following Total Knee Arthroplasty.

INTRODUCTION: Total knee arthroplasty (TKA) is frequently associated with severe, prolonged postsurgical pain, and therefore local anesthetic-based peripheral nerve blocks are commonly used for postoperative analgesia. Cryoneurolysis involves the use of freezing temperatures to provide a reversible sensory (and motor) block with a duration measured in weeks and months, more commensurate with the typical period of post-TKA pain. We therefore conducted a randomized controlled pilot study to evaluate the use of this modality for the treatment of pain following TKA to (1) determine the feasibility of and optimize the study protocol for a subsequent definitive clinical trial; and (2) estimate analgesia and opioid reduction within the first 3 postoperative weeks. METHODS: A convenience sample of 16 patients undergoing primary TKA with a single-injection and/or continuous adductor canal nerve block were randomized to receive either active cryoneurolysis or a sham procedure targeting the infrapatellar branch of the saphenous nerve, in a participant-masked fashion. This was a pilot study with a relatively small number of participants, and therefore resulting data were not analyzed statistically. RESULTS: Compared with participants receiving sham, the active treatment group reported slightly lower average and worst pain scores as well as opioid consumption and sleep disturbances due to pain at a majority of postoperative time points between postoperative days (POD) 4-21. CONCLUSIONS: Preoperative ultrasound-guided cryoneurolysis of the infrapatellar branch of the saphenous nerve is feasible and may provide analgesic benefits for multiple weeks following TKA. A definitive randomized controlled trial appears warranted.

Superior and Middle Cluneal Nerve Entrapment: A Cause of Low Back and Radicular Pain.

BACKGROUND: The superior and middle cluneal nerves are sources of low back, buttock, and leg pain. These nerves are cutaneous branches of the lateral branches of the dorsal rami of T11- S4. Pain arising from entrapment or dysfunction of one or more of these nerves is called "cluneal nerve syndrome." A clear understanding of the anatomy underlying cluneal nerve syndrome and its treatment has been hampered by the very small size of the cluneal nerves and their complex, varying anatomy. Because of differing methods and foci of investigation, the literature regarding cluneal nerves has been confusing and even contradictory. OBJECTIVES: This paper provides a thorough critical literature review of cluneal nerve anatomy and implications for therapy. STUDY DESIGN: A modified scoping review. METHODS: The bibliographic trail of English language papers on the anatomy and treatment of cluneal nerve syndrome was used to resolve the contradictions that have appeared in some of the anatomic descriptions and, where applicable, to examine their implications for therapy. RESULTS: Recent anatomic and surgical investigations confirm a wider than previously realized range of central nervous system origins of these peripheral nerves, explaining why cluneal nerve dysfunction can cause a wide array of symptoms, including low back, buttock, and/or leg pain or "pseudosciatica." CONCLUSIONS: Cluneal nerve syndrome is characterized by a triad of pain, tender points, and relief with local anesthetic injections. The pain is a deep, aching, poorly localized low back pain with variable involvement of the buttocks and/or legs. Tender points are localized at the iliac crest or caudal to the posterior superior iliac spine. Muscle weakness and dermatomal sensory changes are absent in cluneal nerve syndrome. If the pain returns after injections, neuroablation, nerve stimulation, or surgical release may be needed.

Fourth Wave of Opioid (Illicit Drug) Overdose Deaths and Diminishing Access to Prescription Opioids and Interventional Techniques: Cause and Effect.

BACKGROUND: In the midst of the COVID-19 pandemic, data has shown that age-adjusted overdose death rates involving synthetic opioids, psychostimulants, cocaine, and heroin have been increasing, including prescription opioid deaths, which were declining, but, recently, reversing the trends. Contrary to widely held perceptions, the problem of misuse, abuse, and diversion of prescription opioids has been the least of all the factors in recent years. Consequently, it is important to properly distinguish between the role of illicit and prescription opioids in the current opioid crisis. Multiple efforts have been based on consensus on administrative policies for certain harm reduction strategies for individuals actively using illicit drugs and reducing opioid prescriptions leading to curbing of medically needed opioids, which have been ineffective. While there is no denial that prescription opioids can be misused, abused, and diverted, the policies have oversimplified the issue by curbing prescription opioids and the pendulum has swung too far in the direction of severely limiting prescription opioids, without acknowledgement that opioids have legitimate uses for persons suffering from chronic pain. Similar to the opioid crisis, interventional pain management procedures have been affected by various policies being applied to reduce overuse, abuse, and finally utilization. Medical policies have been becoming more restrictive with reduction of access to certain procedures, with the pendulum swinging too far in the direction of limiting interventional techniques. Recent utilization assessments have shown a consistent decline for most interventional techniques, with a 18.7% decrease from 2019 to 2020. The causes for these dynamic changes are multifactorial likely including the misapplication of the 2016 Centers for Disease Control and Prevention (CDC) guidelines for prescribing opioids for chronic pain, the relative ease of access to illicit synthetic opioids and more recently issues related to the COVID-19 pandemic. In addition, recent publications have shown association of dose tapering with overdose or mental health crisis among patients prescribed long-term opioids. These findings are leading to the hypothesis that federal guidelines may inadvertently be contributing to an increase in overall opioid deaths and diminished access to interventional techniques. Together, these have resulted in a fourth wave of the opioid epidemic. METHODS: A narrative review. RESULTS: The fourth wave results from a confluence of multiple factors, including misapplication of CDC guidelines, the increased availability of illicit drugs, the COVID-19 pandemic, and policies reducing access to interventional procedures. The CDC guidelines and subsequent regulatory atmosphere have led to aggressive tapering up to and including, at times, the overall reduction or stoppage of opioid prescriptions. Forced tapering has been linked to an increase of 69% for overdoses and 130% for mental health crisis. The data thus suggests that the diminution in access to opioid prescriptions may be occurring simultaneously with an increase in illicit narcotic use.Combined with CDC guidelines, the curbing of opioid prescriptions to medically needed individuals, among non-opioid treatments, interventional techniques have been affected with declining utilization rates and medical policies reducing access to such modalities. CONCLUSION: The opioid overdose waves over the past three decades have resulted from different etiologies. Wave one was associated with prescription opioid overdose deaths and wave two with the rise in heroin and overdose deaths from 1999 to 2013. Wave three was associated with a rise in synthetic opioid overdose deaths. Sadly, wave four continues to escalate with increasing number of deaths as a confluence of factors including the CDC guidelines, the COVID pandemic, increased availability of illicit synthetic opioids and the reduction of access to interventional techniques, which leads patients to seek remedies on their own.

Insulin Resistance is Associated with Central Pain in Patients with Fibromyalgia.

BACKGROUND: Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to insulin. IR has been associated with multiple conditions, including chronic pain. Fibromyalgia (FM) is one of the common generalized chronic painful conditions with an incidence rate affecting 3% to 6% of the population. Substantial interest and investigation into FM continue to generate  many hypotheses.The relationship between IR and FM has not been explored. IR is known to cause abnormalities in the cerebral microvasculature, leading to focal hypoperfusion. IR also has been shown to cause cognitive impairment in FM patients, as in parkinsonism. As demonstrated by advanced imaging methods, similar brain perfusion abnormalities occur in the brain of patients with FM as with IR. OBJECTIVES: To determine the potential association between FM and IR. SETTING: Subspecialty pain medicine clinics. STUDY DESIGN: Observational cross-sectional study. METHODS: Laboratory data was extracted through a retrospective review of medical records from patients who had met the American College of Rheumatology (ACR) criteria for FM. The Hemoglobin A1c (HbA1c) values from 33 patients with FM were compared with the means of the glycated HbA1c levels of 2 control populations. In addition, established indices of IR [Quantitative Insulin Sensitivity Check Index (QUICKI) and the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)] were calculated in a subgroup of patients in whom the analytes necessary for these calculations were available. To assess for confounding factors, the associations between HbA1c, QUICKI, HOMA-IR, fasting insulin levels, and glucose, after controlling for age, were explored by multiple analyses of variance with relation to gender and ethnicity. RESULTS: We found an association between IR and FM that was independent of age, gender, and ethnicity. We found that patients with FM belong to a distinct population that can be segregated from the control groups by their HbA1c levels, a surrogate marker of IR. This was demonstrated by analyzing the data after introducing an age correction into a linear regression model. This strategy showed significant differences between patients with FM and control subjects (P < 0.0001 and P  = 0.0002, for 2 separate control populations, respectively). A subgroup analysis using the QUICKI and HOMA-IR showed that all patients with FM in this subgroup (100%) exhibited laboratory abnormalities pointing to IR. LIMITATIONS: Small observational cross-sectional study. There are also intrinsic limitations that are attributed to cross-sectional studies. CONCLUSION: The association demonstrated in this study warrant further investigation, including the pursuit of randomized, double-blind clinical trials to determine the effect of improving insulin sensitivity in FM related pain scores. Such studies could unveil a potential pathogenetic relationship between FM, central pain, and IR. Based on these initial findings, we present the hypothesis that IR may underlie pathological mechanisms leading to central pain. If confirmed, this may lead to a paradigm shift in the management of central pain.

Epidural Interventions in the Management of Chronic Spinal Pain: American Society of Interventional Pain Physicians (ASIPP) Comprehensive Evidence-Based Guidelines.

BACKGROUND: Chronic spinal pain is the most prevalent chronic disease with employment of multiple modes of interventional techniques including epidural interventions. Multiple randomized controlled trials (RCTs), observational studies, systematic reviews, and guidelines have been published. The recent review of the utilization patterns and expenditures show that there has been a decline in utilization of epidural injections with decrease in inflation adjusted costs from 2009 to 2018. The American Society of Interventional Pain Physicians (ASIPP) published guidelines for interventional techniques in 2013, and guidelines for facet joint interventions in 2020. Consequently, these guidelines have been prepared to update previously existing guidelines. OBJECTIVE: To provide evidence-based guidance in performing therapeutic epidural procedures, including caudal, interlaminar in lumbar, cervical, and thoracic spinal regions, transforaminal in lumbar spine, and percutaneous adhesiolysis in the lumbar spine. METHODS: The methodology utilized included the development of objective and key questions with utilization of trustworthy standards. The literature pertaining to all aspects of epidural interventions was viewed with best evidence synthesis of available literature and  recommendations were provided. RESULTS: In preparation of the guidelines, extensive literature review was performed. In addition to review of multiple manuscripts in reference to utilization, expenditures, anatomical and pathophysiological considerations, pharmacological and harmful effects of drugs and procedures, for evidence synthesis we have included 47 systematic reviews and 43 RCTs covering all epidural interventions to meet the objectives.The evidence recommendations are as follows: Disc herniation: Based on relevant, high-quality fluoroscopically guided epidural injections, with or without steroids, and results of previous systematic reviews, the evidence is Level I for caudal epidural injections, lumbar interlaminar epidural injections, lumbar transforaminal epidural injections, and cervical interlaminar epidural injections with strong recommendation for long-term effectiveness.The evidence for percutaneous adhesiolysis in managing disc herniation based on one high-quality, placebo-controlled RCT is Level II with moderate to strong recommendation for long-term improvement in patients nonresponsive to conservative management and fluoroscopically guided epidural injections. For thoracic disc herniation, based on one relevant, high-quality RCT of thoracic epidural with fluoroscopic guidance, with or without steroids, the evidence is Level II with moderate to strong recommendation for long-term effectiveness.Spinal stenosis: The evidence based on one high-quality RCT in each category the evidence is Level III to II for fluoroscopically guided caudal epidural injections with moderate to strong recommendation and Level II for fluoroscopically guided lumbar and cervical interlaminar epidural injections with moderate to strong recommendation for long-term effectiveness.The evidence for lumbar transforaminal epidural injections is Level IV to III with moderate recommendation with fluoroscopically guided lumbar transforaminal epidural injections for long-term improvement. The evidence for percutaneous adhesiolysis in lumbar stenosis based on relevant, moderate to high quality RCTs, observational studies, and systematic reviews is Level II with moderate to strong recommendation for long-term improvement after failure of conservative management and fluoroscopically guided epidural injections. Axial discogenic pain: The evidence for axial discogenic pain without facet joint pain or sacroiliac joint pain in the lumbar and cervical spine with fluoroscopically guided caudal, lumbar and cervical interlaminar epidural injections, based on one relevant high quality RCT in each category is Level II with moderate to strong recommendation for long-term improvement, with or without steroids. Post-surgery syndrome: The evidence for lumbar and cervical post-surgery syndrome based on one relevant, high-quality RCT with fluoroscopic guidance for caudal and cervical interlaminar epidural injections, with or without steroids, is Level II with moderate to strong recommendation for long-term improvement. For percutaneous adhesiolysis, based on multiple moderate to high-quality RCTs and systematic reviews, the evidence is Level I with strong recommendation for long-term improvement after failure of conservative management and fluoroscopically guided epidural injections. LIMITATIONS: The limitations of these guidelines include a continued paucity of high-quality studies for some techniques and various conditions including spinal stenosis, post-surgery syndrome, and discogenic pain. CONCLUSIONS: These epidural intervention guidelines including percutaneous adhesiolysis were prepared with a comprehensive review of the literature with methodologic quality assessment and determination of level of evidence with strength of recommendations.

Ultrasound-guided percutaneous intercostal cryoanalgesia for multiple weeks of analgesia following mastectomy: a case series.

BACKGROUND: Acute post-mastectomy pain is frequently challenging to adequately treat with local anesthetic-based regional anesthesia techniques due to its relatively long duration measured in multiple weeks. CASE: We report three cases in which preoperative ultrasound-guided percutaneous intercostal nerve cryoneurolysis was performed to treat pain following mastectomy. Across all postoperative days and all three patients, the mean pain score on the numeric rating scale was 0 for each day. Similarly, no patient required any supplemental opioid analgesics during the entire postoperative period; and, no patient reported insomnia or awakenings due to pain at any time point. This was a significant improvement over historic cohorts. CONCLUSIONS: Ultrasound-guided percutaneous cryoanalgesia is a potential novel analgesic modality for acute pain management which has a duration that better-matches mastectomy than other currently-described techniques. Appropriately powered randomized, controlled clinical trials are required to demonstrate and quantify both potential benefits and risks.

Is insulin resistance the cause of fibromyalgia? A preliminary report.

Fibromyalgia (FM) is one of the most frequent generalized pain disorders with poorly understood neurobiological mechanisms. This condition accounts for an enormous proportion of healthcare costs. Despite extensive research, the etiology of FM is unknown and thus, there is no disease modifying therapy available for this condition. We show that most (if not all) patients with FM belong to a distinct population that can be segregated from a control group by their glycated hemoglobin A1c (HbA1c) levels, a surrogate marker of insulin resistance (IR). This was demonstrated by analyzing the data after introducing an age stratification correction into a linear regression model. This strategy showed highly significant differences between FM patients and control subjects (p < 0.0001 and p = 0.0002, for two separate control populations, respectively). A subgroup of patients meeting criteria for pre-diabetes or diabetes (patients with HbA1c values of 5.7% or greater) who had undergone treatment with metformin showed dramatic improvements of their widespread myofascial pain, as shown by their scores using a pre and post-treatment numerical pain rating scale (NPRS) for evaluation. Although preliminary, these findings suggest a pathogenetic relationship between FM and IR, which may lead to a radical paradigm shift in the management of this disorder.

Nerve Entrapment Headaches at the Temple: Zygomaticotemporal and/or Auriculotemporal Nerve?

BACKGROUND: Temple headaches are common, yet the anatomic etiology of headaches in this region is often confusing. One possible cause of temple headaches is dysfunction of the auriculotemporal nerve (ATN), a branch of the third division of the trigeminal nerve. However, the site of pain is often anterior to the described path of the ATN, and corresponds more closely to a portion of the path of a small branch of the second division of the trigeminal nerve called the zygomaticotemporal nerve (ZTN). OBJECTIVES: We present the anatomic and clinical differences between these 2 nerves and describe treatment approaches. Diagnosis is made by physical examination of the temporal fossa and the temporomandibular joint, and injection of local anesthetic over the tenderest nerve. RESULTS: In general, treatments of headaches that generated from the peripheral nerve attempt to neutralize the pain origin using surgical or interventional pain techniques to reduce nerve irritation and subsequently deactivate stimulated migraine centers. CONCLUSIONS: Treatment of temporal nerve entrapment includes medications, nerve injections, dental appliances, cryoneuroablation, chemical neurolysis, neuromodulation, and surgical decompression. KEY WORDS: Headache, migraine, trigeminal nerve, Frey's syndrome, zygomaticotemporal nerve, auriculotemporal nerve, temple pain, jaw pain, ear pain, tooth pain.

Responsible, Safe, and Effective Use of Biologics in the Management of Low Back Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines.

BACKGROUND: Regenerative medicine is a medical subspecialty that seeks to recruit and enhance the body's own inherent healing armamentarium in the treatment of patient pathology. This therapy's intention is to assist in the repair, and to potentially replace or restore damaged tissue through the use of autologous or allogenic biologics. This field is rising like a Phoenix from the ashes of underperforming conventional therapy midst the hopes and high expectations of patients and medical personnel alike. But, because this is a relatively new area of medicine that has yet to substantiate its outcomes, care must be taken in its public presentation and promises as well as in its use. OBJECTIVE: To provide guidance for the responsible, safe, and effective use of biologic therapy in the lumbar spine. To present a template on which to build standardized therapies using biologics. To ground potential administrators of biologics in the knowledge of the current outcome statistics and to stimulate those interested in providing biologic therapy to participate in high quality research that will ultimately promote and further advance this area of medicine. METHODS: The methodology used has included the development of objectives and key questions. A panel of experts from various medical specialties and subspecialties as well as differing regions collaborated in the formation of these guidelines and submitted (if any) their appropriate disclosures of conflicts of interest. Trustworthy standards were employed in the creation of these guidelines. The literature pertaining to regenerative medicine, its effectiveness, and adverse consequences was thoroughly reviewed using a best evidence synthesis of the available literature. The grading for recommendation was provided as described by the Agency for Healthcare Research and Quality (AHRQ). SUMMARY OF EVIDENCE: Lumbar Disc Injections: Based on the available evidence regarding the use of platelet-rich plasma (PRP), including one high-quality randomized controlled trial (RCT), multiple moderate-quality observational studies, a single-arm meta-analysis and evidence from a systematic review, the qualitative evidence has been assessed as Level III (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best-evidence synthesis. Based on the available evidence regarding the use of medicinal signaling/ mesenchymal stem cell (MSCs) with a high-quality RCT, multiple moderate-quality observational studies, a single-arm meta-analysis, and 2 systematic reviews, the qualitative evidence has been assessed as Level III (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Lumbar Epidural Injections Based on one high-quality RCT, multiple relevant moderate-quality observational studies and a single-arm meta-analysis, the qualitative evidence has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Lumbar Facet Joint Injections Based on one high-quality RCT and 2 moderate-quality observational studies, the qualitative evidence for facet joint injections with PRP has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. Sacroiliac Joint Injection Based on one high-quality RCT, one moderate-quality observational study, and one low-quality case report, the qualitative evidence has been assessed as Level IV (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis. CONCLUSION: Based on the evidence synthesis summarized above, there is Level III evidence for intradiscal injections of PRP and MSCs, whereas the evidence is considered Level IV for lumbar facet joint, lumbar epidural, and sacroiliac joint injections of PRP, (on a scale of Level I through V) using a qualitative modified approach to the grading of evidence based on best evidence synthesis.Regenerative therapy should be provided to patients following diagnostic evidence of a need for biologic therapy, following a thorough discussion of the patient's needs and expectations, after properly educating the patient on the use and administration of biologics and in full light of the patient's medical history. Regenerative therapy may be provided independently or in conjunction with other modalities of treatment including a structured exercise program, physical therapy, behavioral therapy, and along with the appropriate conventional medical therapy as necessary. Appropriate precautions should be taken into consideration and followed prior to performing biologic therapy. Multiple guidelines from the Food and Drug Administration (FDA), potential limitations in the use of biologic therapy and the appropriate requirements for compliance with the FDA have been detailed in these guidelines. KEY WORDS: Regenerative medicine, platelet-rich plasma, medicinal signaling cells, mesenchymal stem cells, stromal vascular fraction, bone marrow concentrate, chronic low back pain, discogenic pain, facet joint pain, Food and Drug Administration, minimal manipulation, evidence synthesis.

Ultrasound-Guided Percutaneous Cryoneurolysis for Postoperative Analgesia After Limb Amputation: A Case Series.

Pain after limb amputation is frequently challenging to adequately treat with local anesthetic-based regional anesthesia techniques due to its relatively long duration. Furthermore, uncontrolled pain in the immediate postoperative period is associated with persistent postsurgical pain, and frequently phantom limb pain. Cryoneurolysis is an alternative regional analgesic method to local anesthesia-based techniques. We report 3 cases in which ultrasound-guided percutaneous cryoneurolysis was performed in the perioperative period of limb amputation. All reported profound analgesia in the postoperative period without persistent postsurgical residual limb or phantom pain in the following months. No adverse events associated with the cryoneurolysis procedure occurred.

Ultrasound-guided percutaneous cryoneurolysis providing postoperative analgesia lasting many weeks following a single administration: a replacement for continuous peripheral nerve blocks?: a case report.

Cryoneurolysis entails using low temperatures to reversibly ablate nerves, with a subsequent analgesia duration measured in weeks or months. Previously, clinical applications for acute pain were limited because treatment originally required exposing the target nerve surgically. However, three developments have now made it possible to provide prolonged postoperative analgesia by cryoneurolysis: 1) new portable, hand-held cryoneurolysis devices, 2) ultrasound machine proliferation, and, 3) anesthesiologists trained in ultrasound-guided peripheral nerve block administration. This report is the first to describe the use of a single preoperative administration of ultrasound-guided percutaneous cryoneurolysis to provide multiple weeks of analgesia following shoulder rotator cuff repair and total knee arthroplasty. Considering the significant benefits of cryoanalgesia relative to continuous peripheral nerve blocks (e.g., lack of catheter/pump care, extremely long duration), this analgesic modality may be a practical alternative for the treatment of prolonged post-surgical pain in a select group of surgical patients.

Ultrasound-Guided Percutaneous Cryoneurolysis for Acute Pain Management: A Case Report.

We report 3 different cases in which ultrasound-guided percutaneous cryoneurolysis was performed to treat acute pain: 1 patient with refractory incisional pain after percutaneous nephrolithotomy; 1 patient with burns to the foot; and 1 patient with pain from iliac crest grafting. Acute pain associated with surgery or injury is a challenge to treat with local anesthetic-based regional anesthesia techniques when the anticipated pain duration exceeds a few days. Cryoneurolysis is an alternative analgesic method that utilizes extremely cold temperatures to reversibly ablate peripheral nerves and is potentially a novel method for acute pain management.

Full-Endoscopic Assisted Lumbar Decompressive Surgery Performed in an Outpatient, Ambulatory Facility: Report of 5 Years of Complications and Risk Factors.

BACKGROUND: Minimally invasive surgery (MIS) technique is becoming the standard tissue sparing approach for decompression of lumbar central and lateral recess stenosis, intervertebral disc herniation, or any situation that would have required extensive open decompression laminectomy. Full-endoscopic or arthroscopic assisted surgery is arguably the "ultra-MIS" approach to lumbar spinal pathology. Age and body mass index (BMI) are significant risk factors to be considered in full-endoscopic assisted ultra-MIS. With limited medical literature published on complication rates for MIS, reports on the ultra-MIS approach are even scarcer for free-standing, outpatient ambulatory settings. OBJECTIVES: The primary goal of this study is to compare outcomes for full-endoscopic assisted ultra-MIS lumbar decompression surgical techniques, performed in a free-standing, outpatient ambulatory facility, with other spine surgery techniques. STUDY DESIGN: This is a Western Institutional Review Board (WIRB)-approved retrospective review of prospectively collected patient demographic and outcomes data for full-endoscopic assisted interlaminar and transforaminal lumbar decompressive surgery. SETTING: Free-standing, outpatient ambulatory surgery facility. METHODS: A population of 178 patients, whose age ranged between 16 and 90 years old (mean 45.5 years), with a variety of clinical presentation of symptoms underwent lumbar decompressive surgery using an interlaminar or transforaminal full-endoscopic assisted approach between January 2011 and December 2015. Operative (OR) time, complication rates, estimated blood loss, preoperative and postoperative leg and back VAS, and patient satisfaction ratings at 6, 9, and 12 months post operation are reported. RESULTS: Age is a significant predictor of OR time; older patients generally have longer surgeries. BMI does not have statistically significant effect on OR time; heavier patients have similar OR time as other cohorts. There were no reportable intra-operative complications in this series of 178 patients. There were 3 major (1.69%) and three 3 (1.69%) postoperative complications. The 3 major complications were all incidences of early postoperative reherniation that resulted in re-operation. The minor complications included 2 cases of sympathetically mediated pain syndrome and one case of postanesthetic transient urinary retention. About 95% of patients had less than 5 mL of blood loss. No patients lost more than 35 mL of blood during surgery. Visual analog scale (VAS) score dropped from 7 to 3, on a scale of 0 to 10 with 10 being the worst pain imaginable, within 2 months postoperative. On average, 70% to 80% of patients were satisfied or greatly satisfied with the surgery, and 85% to 92% of patients would recommend this type of surgery. LIMITATIONS: Retrospective study. CONCLUSIONS: Full-endoscopic assisted ultra-MIS technique is a viable option for lumbar decompressive surgery in a free-standing, outpatient ambulatory facility. The patient population in this study demonstrates its safety, efficacy, and effectiveness for treatment of various lumbar pathologies. It is particularly relevant that age and obesity are not contra-indications.Key words: Full-endoscopic, minimally invasive spine surgery, postoperative complications, lumbar discectomy, lumbar decompression, lumbar disc herniation, spinal stenosis, endoscopic discectomy, ultra-MIS, arthroscopic.

Responsible, Safe, and Effective Prescription of Opioids for Chronic Non-Cancer Pain: American Society of Interventional Pain Physicians (ASIPP) Guidelines.

BACKGROUND: Opioid use, abuse, and adverse consequences, including death, have escalated at an alarming rate since the 1990s. In an attempt to control opioid abuse, numerous regulations and guidelines for responsible opioid prescribing have been developed by various organizations. However, the US opioid epidemic is continuing and drug dose deaths tripled during 1999 to 2015. Recent data show a continuing increase in deaths due to natural and semisynthetic opioids, a decline in methadone deaths, and an explosive increase in the rates of deaths involving other opioids, specifically heroin and illicit synthetic fentanyl. Contrary to scientific evidence of efficacy and negative recommendations, a significant proportion of physicians and patients (92%) believe that opioids reduce pain and a smaller proportion (57%) report better quality of life. In preparation of the current guidelines, we have focused on the means to reduce the abuse and diversion of opioids without jeopardizing access for those patients suffering from non-cancer pain who have an appropriate medical indication for opioid use. OBJECTIVES: To provide guidance for the prescription of opioids for the management of chronic non-cancer pain, to develop a consistent philosophy among the many diverse groups with an interest in opioid use as to how appropriately prescribe opioids, to improve the treatment of chronic non-cancer pain and to reduce the likelihood of drug abuse and diversion. These guidelines are intended to provide a systematic and standardized approach to this complex and difficult arena of practice, while recognizing that every clinical situation is unique. METHODS: The methodology utilized included the development of objectives and key questions. The methodology also utilized trustworthy standards, appropriate disclosures of conflicts of interest, as well as a panel of experts from various specialties and groups. The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed, with a best evidence synthesis of the available literature, and utilized grading for recommendation as described by the Agency for Healthcare Research and Quality (AHRQ).Summary of Recommendations:i. Initial Steps of Opioid Therapy 1. Comprehensive assessment and documentation. (Evidence: Level I; Strength of Recommendation: Strong) 2. Screening for opioid abuse to identify opioid abusers. (Evidence: Level II-III; Strength of Recommendation: Moderate) 3. Utilization of prescription drug monitoring programs (PDMPs). (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 4. Utilization of urine drug testing (UDT). (Evidence: Level II; Strength of Recommendation: Moderate) 5. Establish appropriate physical diagnosis and psychological diagnosis if available. (Evidence: Level I; Strength of Recommendation: Strong) 6. Consider appropriate imaging, physical diagnosis, and psychological status to collaborate with subjective complaints. (Evidence: Level III; Strength of Recommendation: Moderate) 7. Establish medical necessity based on average moderate to severe (≥ 4 on a scale of 0 - 10) pain and/or disability. (Evidence: Level II; Strength of Recommendation: Moderate) 8. Stratify patients based on risk. (Evidence: Level I-II; Strength of Recommendation: Moderate) 9. Establish treatment goals of opioid therapy with regard to pain relief and improvement in function. (Evidence: Level I-II; Strength of Recommendation: Moderate) 10. Obtain a robust opioid agreement, which is followed by all parties. (Evidence: Level III; Strength of Recommendation: Moderate)ii. Assessment of Effectiveness of Long-Term Opioid Therapy 11. Initiate opioid therapy with low dose, short-acting drugs, with appropriate monitoring. (Evidence: Level II; Strength of Recommendation: Moderate) 12. Consider up to 40 morphine milligram equivalent (MME) as low dose, 41 to 90 MME as a moderate dose, and greater than 91 MME as high dose. (Evidence: Level II; Strength of Recommendation: Moderate) 13. Avoid long-acting opioids for the initiation of opioid therapy. (Evidence: Level I; Strength of Recommendation: Strong) 14. Recommend methadone only for use after failure of other opioid therapy and only by clinicians with specific training in its risks and uses, within FDA recommended doses. (Evidence: Level I; Strength of Recommendation: Strong) 15. Understand and educate the patients of the effectiveness and adverse consequences. (Evidence: Level I; Strength of Recommendation: Strong) 16. Similar effectiveness for long-acting and short-acting opioids with increased adverse consequences of long-acting opioids. (Evidence: Level I-II; Strength of recommendation: Moderate to strong) 17. Periodically assess pain relief and/or functional status improvement of ≥ 30% without adverse consequences. (Evidence: Level II; Strength of recommendation: Moderate) 18. Recommend long-acting or high dose opioids only in specific circumstances with severe intractable pain. (Evidence: Level I; Strength of Recommendation: Strong)iii. Monitoring for Adherence and Side Effects 19. Monitor for adherence, abuse, and noncompliance by UDT and PDMPs. (Evidence: Level I-II; Strength of Recommendation: Moderate to strong) 20. Monitor patients on methadone with an electrocardiogram periodically. (Evidence: Level I; Strength of Recommendation: Strong). 21. Monitor for side effects including constipation and manage them appropriately, including discontinuation of opioids when indicated. (Evidence: Level I; Strength of Recommendation: Strong)iv. Final Phase 22. May continue with monitoring with continued medical necessity, with appropriate outcomes. (Evidence: Level I-II; Strength of Recommendation: Moderate) 23. Discontinue opioid therapy for lack of response, adverse consequences, and abuse with rehabilitation. (Evidence: Level III; Strength of Recommendation: Moderate) CONCLUSIONS: These guidelines were developed based on comprehensive review of the literature, consensus among the panelists, in consonance with patient preferences, shared decision-making, and practice patterns with limited evidence, based on randomized controlled trials (RCTs) to improve pain and function in chronic non-cancer pain on a long-term basis. Consequently, chronic opioid therapy should be provided only to patients with proven medical necessity and stability with improvement in pain and function, independently or in conjunction with other modalities of treatments in low doses with appropriate adherence monitoring and understanding of adverse events.Key words: Chronic pain, persistent pain, non-cancer pain, controlled substances, substance abuse, prescription drug abuse, dependency, opioids, prescription monitoring, drug testing, adherence monitoring, diversionDisclaimer: The guidelines are based on the best available evidence and do not constitute inflexible treatment recommendations. Due to the changing body of evidence, this document is not intended to be a "standard of care."

Novel cryoneurolysis device for the treatment of sensory and motor peripheral nerves.

INTRODUCTION: Cryoneurolysis is the direct application of low temperatures to reversibly ablate peripheral nerves to provide pain relief. Recent development of a handheld cryoneurolysis device with small gauge probes and an integrated skin warmer broadens the clinical applications to include treatment of superficial nerves, further enabling treatments for pre-operative pain, post-surgical pain, chronic pain, and muscle movement disorders. AREAS COVERED: Cryoneurolysis is the direct application of cold temperatures to a peripheral nerve, resulting in reversible ablation due to Wallerian degeneration and nerve regeneration. Use over the last 50 years attests to a very low incidence of complications and adverse effects. Cryoprobes have traditionally been applied through a surgical incision; but, recent technical advances allow percutaneous administration. A new hand-held device is now approved for use within the United States. Cryoneurolysis has been used to treat postoperative and chronic pain states as well as spasticity. Expert commentary: Changes in the US healthcare system such as a push for the reduction of opioid use and the incorporation of Diagnostic Related Group codes, as well as recent technological advances including a handheld unit that allows for treatment of superficial nerves while protecting the skin from damage, may contribute to the resurgence of cryoneurolysis for the treatment of peripheral nerves.