Osteoarthritis is a highly prevalent pain disorder involving erosion of articular cartilage and damage to subchondral bone and surrounding cell tissue. The avascularity of articular cartilage and limited regeneration of chondrocytes create limitations in self-healing. Current therapies include pharmacologic agents such as NSAIDs and opioids as well as surgical procedures such as joint replacements, none of which serve to reverse the damage to articular cartilage despite the complications they carry. Emerging evidence for the use of stem cell therapy for chondrogenesis has led to great interest and the opening of stem cell centers nationwide for the treatment of osteoarthritis. It is prudent to review the evidence thus far of the efficacy of these treatments to better inform our patients of their options.

The first generation of stem cell therapy involved bone marrow-derived mesenchymal stem cells (MSC), which were associated with donor site morbidity and pain and low cell number on harvest. These issues led to the investigation into alternative sources for MSCs, including periosteum, muscle, synovial membrane and adipose tissue. Since MSCs have the ability to differentiate into chondrocytes, osteoblasts, myoblasts, adipocytes and fibroblasts depending on the conditions under which they are stimulated, they offer great potential for tissue regeneration of various kinds.

Stromal vascular fraction (SVF) of adipose tissue has become the most popular substrate for the study of stem cell therapy for osteoarthritis, given that the stem cells contained within are abundant in number and easy to harvest. Despite concern that adipose derived mesenchymal stem cells (ADSCs) have limited chondrogenic potential, recent evidence demonstrate their ability to be induced along chondrocyte pathways under specific conditions, and animal models confirmed their chondrogenesis effect in vivo.

A metanalysis of human clinical studies on the effects of ADSCs on osteoarthritis was published earlier this year. All studies prepared ADSCs in the form of stromal vascular fraction (SVF), the component of lipoaspirate that contains ADSCs, pericytes, vascular adventitia cells, fibroblasts, preadipocytes, monocytes, macrophages and red blood cells. The 16 studies varied regarding site and time of SVF collection via liposuction, site of treatment (e.g. knees vs ankles), and whether the SVF was used with biologics such as platelet rich plasma (PRP) and fibrin.

All 16 studies reported favorable clinical outcomes, i.e. pain and function scores. 5 studies reported patient satisfaction rate, all of which were above 90%. 8 studies also reported radiological outcomes via MRI or X-ray, with mixed outcome measures showing an overall promising trend. MRI findings included improved cartilage thickness in most of the studies. Complication rates were reported in 7 studies, which were minor and included swelling at the procedural site.

The favorable clinical and radiographical outcomes shown in the metanalysis should be taken with a grain of salt, as there was high variability in all studies regarding data collected and use of biological adjuvants. This makes cross-study comparison difficult and leads to possible confounding of the actual weight of ADSCs’ effect. Biologics such as platelet rich plasma (PRP) have been shown to contain growth factors which potentially increase chondrocyte viability and differentiation, and may improve the synthetic capacity of MSCs. There was also significant variability in the methods used to prepare the ADSCs, as well as the methods for assessing chondrogenic potential of the harvested SVF. In the studies which reported it, the average percentage of ADSC in the SVF was only 9.2%, with the majority of the injectate being comprised of the other aforementioned SVF components. There was also great intra-study variability in the percentage of ADSC in SVF, with little analysis of possible factors contributing to this such as patient age or methods of preparation.

In summary, stem cell therapy in the treatment of osteoarthritis pain has shown promising results in early clinical trials, however these trials are limited by their lack of procedural standardization and potential biases. It will be worth following further investigations of this treatment modality as procedures are refined to introduce less variability.

References

Dubey NK, Mishra VK, Dubey R, Syed-Abdul S, Wang JR, Wang PD, Deng WP. Combating Osteoarthritis through Stem Cell Therapies by Rejuvenating Cartilage: A Review. Stem Cells Int. 2018 Mar 22;2018:5421019.

Hurley ET, Yasui Y, Gianakos AL, Seow D, Shimozono Y1, Kerkhoffs GMMJ, Kennedy JG. Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2018 Apr 30.

Neuromodulation or Neurostimulation is a promising modality for treating neurological disease (Parkinson’s disease, Tremors, Chronic Pain, seizures) as well as psychiatric disorders (Major Depression, OCD). The basic premise of neuromodulation is that by stimulating deep brain structures, it is possible to disrupt abnormal patterns of brain activity (in people with neurologic disease) and thereby restore normal brain electrical rhythms resulting in improvement and even resolution of symptoms. While the exact mechanism of how Neuromodulation works is not completely understood, it is believed that restoring normal brain electrical activity is essential to improve disease symptoms. Contrary to what many in the general public would think, a typical neurostimulating system is relatively simple in that it consists of only three components: an implantable stimulator generator/pulse generator (IPG), a lead, and extension wiring. Traditional Neuromodulation consists of continuous high-frequency stimulation (known as an open-loop system). While effective in minimizing some symptoms, this method of neuromodulation comes with the drawbacks of causing potential tissue damage from the constant stimulation as well as shortening generator (IPG) battery life to 2-5 years.

In continuous pursuit of a cure, neuromodulation companies/labs are developing increasingly sophisticated brain stimulators. Building off the success of the open-loop system, researchers have developed next generation systems that make stimulation more targeted not only in terms of where, but when stimulation occurs. This new targeted type of therapy where stimulation occurs in response to specific changes in a patient’s electrical brain activity is known as closed-loop neuromodulation. These implantable devices are able to record the electrical activities of many neurons continuously and as a result, determine patterns in the overall neural activity. The specific neural patterns are then able to be utilized as an input signal to the processor in the device that can sync neurostimulation with a specific event.

Consider that an early usage for neuromodulation was treating refractory epilepsy, an event that occurs spontaneously and unpredictably (much like that of a life-threatening cardiac arrhythmia). One could see the similarities between a neuromodulator and Automated Implantable Cardioverter Defibrillator (AICD), and thus the benefits provided by a closed-loop system. Much like how an AICD delivers a shock to stop an abnormal heart rhythm only when it occurs, an implantable closed loop neurostimulator can halt an epileptic seizure by delivering stimulation when it senses the beginning of seizure activity in the brain. While only an analogy, it makes sense that a device that only as beneficial in specific situations would be better to be triggered for that purpose alone.

The transformational benefit of closed loop neuromodulation clearly is a targeted therapy specific to an individual’s electrical brain activity, but other benefits of a closed loop system are still impressive such as a potential decrease in tissue damage as well as an overall decrease in power consumption leading to increased battery life (and subsequently avoiding frequent surgical IPG replacement). The benefits of the closed loop system are now starting to be quantified with early studies are demonstrating promising results with the treatment of epilepsy. A 2018 FDA approved study demonstrated that patients with a closed loop system experienced a 70% median seizure reduction after five years of therapy. This finding as well as numerous other promising ones are validating the benefits of a closed loop system. As a result of its individualization, closed loop neuromodulation can and is now being applied to all types of neuropathology. As the technology continues to be refined the benefits to those suffering will only increase.

Pain management is a crucial component of surgical recovery for any patient, but there are unique concerns and challenges that comes with managing pain in pediatric patients. While the inherent vulnerability of children is deeply felt by clinicians and families alike, postoperative pain is nevertheless undertreated in this population. A major driver of this issue is that many common procedures require little time in the hospital, leaving most of the recovery to happen at home. Neglected postoperative pain creates short-term issues of sleep disruption, stress, and delayed recovery but can also lead to serious long-term consequences, or even disability.¹

A central barrier to effectively managing pain following a procedure is reliably assessing a young patient’s pain level.² This task most often falls to parents and other caregivers, and is deceptively difficult. Research reveals two major challenges in pain reporting: a child’s ability to identify and name their pain, and the reliability of measurement instruments to consistently guide a clinical response. Opioids are unsurprisingly a central tool for effectively treating pain in children. For acute pain in particular, they are a powerful option that can provide uniquely immediate relief. However, there are known risks and side effects associated with opioid use that merit heightened caution when opiods are being used by children. Understanding a child’s experience of pain is key to responding with the appropriate balance of analgesics, and this can place an immense amount of pressure on caregivers at home.

Self-reporting is the clinically preferred way to assess pain in children.³ However, this approach to pain measurement can be difficult among children for reasons that any parent could probably guess—a child may be afraid that sharing about their pain will cause them to return to the hospital, for example, or their social environment might cause them to overstate or understate their pain level. Commonly used instruments take various forms of visual and verbal rating scales, but the evidence is mixed on which tools are the most rigorous and widely applicable across the many developmental stages of childhood.

What if there was a way to solicit a child’s experience of pain through a familiar, less clinical and engaging instrument? This is where the recently developed Panda pain management mobile app is poised to make a difference. The Panda app seeks to improve pediatric postoperative pain management through an engaging and easy-to-use platform. Parents or other caregivers use the app’s walkthrough design to assess and record important aspects of their child’s pain. Then, the app guides them in making decisions about when and how to administer pain medication, tracking when medication is administered to keep families on schedule for future dosages. Users receive medication alerts directly from their phone, much like the many apps families already use to schedule and track their commitments and routines.

Panda was developed by researchers at the University of British Columbia and has already seen promising results in the controlled setting of in-hospital use. Parents piloting the app with the guidance of clinical staff reported that the app was easy to use and could see themselves using it in the home setting.⁴ The app is currently being evaluated for in-home use.

Providing families with an easy-to-navigate tool to not just identify pain in children following surgery, but also connect those pain measurements to a medication schedule, could be an important step in better addressing this neglected area of pain management. Pain management is a complex aspect of clinical care for patients regardless of age, and the special concerns of pediatric patients demand innovation beyond merely adapting adult guidelines for younger patients. There are exciting possibilities for the use of smartphone apps like Panda in better describing and alleviating pain in children. Tools that fit neatly into a familiar routine, like a smartphone app, may reduce some of the stress parents face in managing complex pain without clinical support.

References

[1] Porter FL, Grunau RE, Anand KJ: Long-term effects of pain in infants. J Dev Behav Pediatr 1999; 20:253–61Porter, FL Grunau, RE Anand, KJ

[2] Chou, Roger, et al. “Management of Postoperative Pain: a clinical practice guideline from the American pain society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ committee on regional anesthesia, executive committee, and administrative council.” The Journal of Pain 17.2 (2016): 131-157.

[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983412/

[4] https://www.researchgate.net/publication/316853501_Feasibility_of_Panda_a_Smartphone_Application_Designed_to_Support_Pediatric_Postoperative_Pain_Management_at_Home

Background/description

Herniated Cervical Disc also known as Cervical Radiculopathy (“slipped disc”, “ruptured disc”) is a medical term for the pain (neck and arms), numbness, tingling and weakness associated with a herniated disc in the cervical (neck) region. Patients often undergo significant suffering and reduction in quality of life with this condition. It is the second most common type of disc herniation, following lumbar (back) disc herniation. Cervical disc herniation occurs in the neck region, usually between the lower cervical vertebral bodies but can occur in any disc of the cervical spine. The essence of the condition is a tear in the fibrous outer ring of the disc between vertebrae which then allows for the central component (nucleus pulposus) to protrude out. This nucleus pulposus carries a cascade of inflammatory chemicals that often irritate and compress cervical spinal nerves causing symptoms. This can occur spontaneously or from trauma, lifting, and straining of the neck.

Symptoms of this condition depend on the location and severity of the herniation. In terms of location, there are seven cervical vertebral bodies with discs between them (these are the ones that can herniate) with 2 spinal nerves exiting at each level. Vertebral discs provide support and mobility for the neck region. Severity is often caused by how much of the disc has herniated and subsequently compressed the surrounding cervical spinal nerve. Patients’ symptoms can range from mild sensory changes in the neck and arms: numbness, tingling, paresthesia to sharp shooting pain, muscle weakness, and arm paralysis. Severe symptoms should warrant immediate medical evaluation.

Diagnosis and Management

Diagnosis of cervical disc herniation is a clinical one often resulting from the story (history) provided by the patient and the physical examination findings. Examination includes a thorough neurological examination to uncover motor and sensory changes. This will often lead to the “culprit” cervical nerve root that is impingement by a cervical disc herniation. Other signs include increase in arm reflexes and a maneuver known as Spurling’s, where downward pressure is applied by a physician on a patient’s neck to recreate arm tingling and numbness. There is no “gold standard” for diagnosing cervical disc herniation but often imaging, specifically MRI, is very helpful. Imaging may point to the existence of specific locations of disc protrusion and if correlating with the symptoms may aid in the diagnoses. There is a high degree of variability in the symptoms experienced by patients. Most concerning as worsening pain and weakness in arm. Other possible diagnoses for neck/arm symptoms are nerve entrapment medical conditions such as carpal tunnel (median nerve) syndrome and cubital tunnel (ulnar nerve) syndrome. These can often be diagnosed clinically with the support of a nerve conduction study.

Most cervical disc herniations will heal on their own with conservative measures (include rest, ice, heat, anti-inflammatory medications). Most of the time the symptoms involve pain, numbness, and weakness in the arm. If symptoms do resolve, they often do so in a period of weeks to a couple of months. Otherwise, initial treatment often begins with conservative measures including education, light exercise, medications (short course of anti-inflammatories), physical therapy, body mechanics, cervical traction, and weight control. More invasive treatments include interventional pain injections (cervical epidural steroid injections) and/or surgery (most commonly anterior cervical discectomy and fusion – ACDF). Cervical epidural steroid injections involve depositing a small quantity of steroid and local anesthetic mediation, using X-ray image guidance, onto the affected cervical spine nerve. These may often be repeated every 3-6 months depending on the symptoms. Indications for surgery include patients with ongoing arm pain despite 6-8 weeks of conservative treatment along with signs of motor weakness.

Neuropathic pain is an elusive target for anesthesia pain specialists. A small class of anti-epileptic and antidepressant mediations has been the mainstay of medical therapy for neuropathic pain, and it has been put forward that only one in three patients who suffer from this particularly recalcitrant condition has an analgesic response to treatment.

In searching for potential new therapies for neuropathic pain, selective cannabinoids (synthetic cannabinoids containing only tetrahydrocannabinol [THC]) have emerged in the past decade as a drug class of interest. Cannabinoid receptors play a role in pain modulation by inhibiting pain responses, and also interact with various other receptor systems such as GABA, opiate, serotonergic and adrenergic, many of which are current targets for neuropathic pain medications.

A recent meta-analysis attempted to examine the efficacy of selective cannabinoids in treating neuropathic pain refractory to first and second-line agents. A database search was conducted for randomized control trials (RCT) comparing selective cannabinoids (dronabinol, nabilone, and nabiximols) containing synthetic THC, or a combination of extracted THC and CBD, versus placebo or standard treatment.

11 RCTs were selected for inclusion. All studied neuropathic pain patients, but there was variability in the etiology of this pain and its distribution. Variation also existed in which cannabinoid was used (1 dronabinol trial, 3 nabilone, and 7 nabiximols) and for how long (2 to 15 weeks), as well as the dosages. Primary outcome in all studies was pain score, with a multitude of secondary outcomes including physical function, quality of sleep, anxiety, and patient satisfaction. Not all secondary outcomes were examined across all studies (e.g. only three included physical function).

Metanalysis of the 11 RCTs showed that with regard to the primary outcome of pain scores (measured on the numerical rating scale and measured at least two weeks after therapy initiation), there was a statistically significant but clinically small reduction in pain scores in the selective cannabinoids group (mean difference −0.65 points; 95% CI, −1.06 to −0.23 points; P = .002, I2 = 60%).

For secondary outcomes, quality of sleep and patient satisfaction were significantly improved. Only one of the three studies that examined physical function reported an improvement. Six out of the seven studies that examined quality of sleep found an improvement. Only one of the three studies that examined anxiety reported an improvement. Five of the six studies that examined patient satisfaction reported positive results.

Adverse effects of selective cannabinoids studied by the 11 included RCTs were mostly mild to moderate. Most common were dizziness/lightheadedness, somnolence, and dry mouth. Rarely there were severe adverse effects requiring withdrawal from the trials: confusion (2 patients), headache (1 patient), agitation and paranoid ideation (2 patients).

Overall, the small clinical reduction in pain scores must be weighed against the potential for adverse effects. Sleep quality and patient satisfaction are likely secondary benefits. Weaknesses of this meta-analysis include wide heterogeneity of trials and likely publication bias. Further research is needed to standardize dosages and duration of treatment, as well as better define adverse effects.

References

1. Meng H, Johnston B, Englesakis M, Moulin DE, Bhatia A. Selective cannabinoids for chronic neuropathic pain: a systematic review and meta-analysis [published online May 19, 2017]. Anesth Analg. doi:10.1213/ANE.0000000000002110