However, despite the alarming rate of death from opioid overdose, this problem is not grabbing the headlines from the media for health stakeholders to pay more attention and look for ways to finding lasting solutions to the anomaly.
It is worthy to note that, while many people are addicted to opioids in the form of heroin and synthetic opioids, millions of people are out there, taking an overdose of opioids in the form of pain reliever prescription for chronic pains and other related health issues. Though, opioids are used in the treatment of chronic pain, research has suggested that they may not help relieve pain in the long-term. This has posed a serious threat to public health and economic welfare, not only for the United States but other affected countries as well.
According to the Centers for Disease Control and Prevention, the total “economic burden” of only opioid misuse prescription in the US is estimated as $78.5 billion per year, inclusive of lost productivity, criminal justice involvement, healthcare cost, and addiction treatment.
This article aims to look at how we come to this point, some facts about opioids in the United States, and some useful information about opioid overdose. Read on to uncover them all.
Opioids and Substance Abuse at a Glance.
Opiates, popularly known as narcotics, are commonly prescribed for quick pain relief and sleep inducement. Originally, it is derived from poppy plant seeds or their byproducts. Opiates occur naturally in the form of opium and morphine, but most opiates are synthetic. These drugs became highly addictive because they create an intense sense of euphoria and as well as safeness, when adding it to pain-relieving properties.
Most patients with pain disorders later turn to rely on pharmaceutical opiates like oxycodone and hydrocodone; hence, they become addicted to it. However, opioid overdose has been studied to cause a number of health problems in the users, and these health issues are not limited to serious disorders, but even death. One of the prolonged effects of opioid usages is the brain’s inability to produce endorphins naturally. Endorphins are known to be the body’s natural painkillers.
Initially, around late 1990s, when opioids were becoming popular among the people, pharmaceutical companies came out to allay the fear of the people and reassure the medical community that opiate users would not become addicted to opioids prescribed for pain relief; hence, healthcare service providers started prescribing the drugs to patients at greater rates. Subsequently, this act resulted in a extensive misuse and diversion of these drugs prior to the time it was discovered that opioid prescriptions could actually be highly addictive like other opiates.
Facts about Opioid Prescription and Misuse in America.
The rates of opioid overdose in the United States started increasing in 2017 with over 47,000 citizens died due to misuse of opioids, such as heroin, prescription opioids, illicitly manufactured fentanyl (one of the powerful opioid synthetics). In the same year, this number was estimated 1.7 million and 652,000 Americans suffered from prescription opioid pain relievers and heroin use disorder respectively. The question is, how does it start?
It all starts when the body cannot properly manage and regulate pain again. In this condition, an opiate user may become addicted to the drugs, as the drugs now used to relief their pain and at the same time, create a sense of contentment and happiness in using them. Over time, even after the pains have gone, an opiate user will require more of the substance to reach the same level of high that creates happiness and contentment which they first experienced; hence, the person is already “an opiate addict.” Withdrawing from its use makes it even worse, as their bodies begin to show some unpleasant symptoms that make the user seeking more to relieve the symptoms.
From here, opioid prescription and misuse have turned out to become a public health problem in the United States with alarming rates of death on a daily basis.
Below are some facts about the opioid crisis in the United States:
- According to WQAD Digital Team’s claim of IMS Health’s market research, the number of opioid prescriptions doctors dispensed increased from 112 million to 282 million from 1992 to 2012 respectively. However, according to IQVIA, the number has declined to 236 million in 2016 and further dropped by 10.2% in 2017.
- Centers for Disease Control and Prevention, about 68% of cases of estimated 70,200 drug overdose deaths recorded in 2017 were linked to the use of opioids. This is more than six times compared to that of 1999 (including illegal opioids such as heroin and illicitly manufactured fentanyl and prescription opioids).
- According to a review, about 21 – 29% of patients with chronic pain who take opioids prescription misuse them.
- Another study also claimed that roughly 80% of heroin users initially misused prescription opioids.
- The same study also claimed that about 8 – 12% of opiate users develop an opioid use disorder.
- According to the Centers for Disease Control and Prevention, there is a 30% increase in opioid overdoses in 45 states of the United States between July 2016 to September 2017.
- In another review, opioid overdoses were seen increasing by 70% in the Midwestern region between July 2016 to September 2017.
What is been doing about it?
With over two million opioid dependants in the United States, the U.S. Department of Health and Human Services (HHS) is making efforts to tackle the opioid crisis in America by focusing on five major areas. These include:
- Promoting and enlighten people on the use of overdose-reversing drugs.
- Giving people access to treatment and recovery therapies.
- Offering support for modern research on addiction and pain.
- Promoting public health surveillance to help people understand the epidemic better.
- Enhancing better pain management practices in the country.
In furtherance to the efforts of the U.S. Department of Health and Human Services (HHS), the National Institutes of Health (NIH)’s Director Francis S. Collins in April 2018’s National Rx Drug Abuse and Heroin Summit, announced the launch of a special program referred to HEAL (Helping to End Addiction Long-term) Initiative. HEAL is an aggressive effort set up to expedite scientific solutions to address the opioid crisis in the United States.
Just because media are not paying attention to the opioid crisis in the US does not mean things are working in the medical world. With the alarming rate of opioid overdose and an increasing number of Americans abusing prescription and becoming dependent on opioids, all hands must be on deck to find a lasting solution to the current problem. While different agencies and stakeholders are not relenting on their efforts, more medical developments and approaches are still required to achieve a good result.
Autologous micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis: an update at 3 year follow-up
The management of chondral disease is challenging because of its intrinsic poor healing potential. Biomechanical and biological changes may lead to the loss of tissue homoeostasis, resulting in an accelerated degeneration of the articular surface, eventually leading to end-stage osteoarthritis (OA).
Conservative therapies for the treatment of knee degenerative processes, such as non-pharmacological interventions, systemic drug treatment and intra-articular therapies are used before resorting to surgery; nonetheless, they may offer only short-term benefits. Encouraging preliminary results have been reported using mesenchymal stem cells (MSCs), either alone or in association with surgery. Among the many sources of MSCs, adipose tissue has created a huge interest in the context of cartilage regeneration (Pak et al. 2016; Ruetze and Richter 2014), due to its wide availability, ease to harvest and richness in mesenchymal cell elements within the so called stromal vascular fraction (De Girolamo et al. 2016; Caplan 2008; Caplan and Correa 2011; Caplan and Dennis 2006). Moreover, MSCs from adipose tissue are characterized by marked anti-inflammatory and regenerative properties, which make them an excellent tool for regenerative medicine purposes (De Girolamo et al. 2016; Caplan 2008; Caplan and Correa 2011; Caplan and Dennis 2006). Nevertheless, preparation of autologous MSCs for injection requires ex vivo culture from a good manufacturing practice facility, which makes the process laborious and expensive (Ährlund-Richter et al. 2009; Arcidiacono et al. 2012; Sensebé et al. 2010). An increasing number of adipose tissue-derived cell isolation systems, allowing for minimal manipulation, have been developed in the last years. We previously reported the safety and feasibility of autologous micro-fragmented adipose tissue as adjuvant for the surgical treatment of diffuse degenerative chondral lesions at 1 year follow-up (Russo et al. 2017). Here we present the outcomes of the same cohort of patients evaluated at 3 year follow-up.
The original study was approved by the Ethics Committee of Verona and Rovigo – Italy (protocol n° 10,227, March 1st, 2016). An extension of the study protocol has been conceded by the same authority to evaluate the results at 3 years (protocol n° 14,505, March 14th 2018) and written informed consent was obtained from all patients.
Study design and population, surgical techniques, post-op rehabilitation protocol, safety and clinical evaluation were previously described (Russo et al. 2017). Briefly, 30 patients, affected by diffuse degenerative chondral lesions of different degrees of severity, were treated with autologous and micro-fragmented adipose tissue between 1stJanuary 2014 and 31st December 2014. Of these 30 patients, 24 (80%) also had an associated surgery (ACL/LCL reconstruction, high tibial osteotomy, meniscectomy), while six (20%) underwent arthroscopy alone. For the 3 year follow-up all the patients were re-contacted and clinically evaluated by the same clinicians.
Of the 30 patients treated with autologous micro-fragmented adipose tissue, eight also had meniscal surgery, five plate removal, three osteotomy, two ligament surgery, two microfractures, and four other surgical procedures. The remaining six had arthroscopy alone. Despite the heterogeneity of the associated surgical procedures all the patients shared the presence of chondral lesions of different degrees of severity (Russo et al. 2017).
Table 1: Background data of the failures (n = 7)
FC femoral condyle, TP tibial plateau, PF patellofemoral.
No adverse events, lipodystrophy cases at the harvesting site nor atypical inflammatory reactions at the joint level were reported in the 3 year period for all the 29 patients.
|Grade chondropathy (ICRS classification)|
FC femoral condyle, TP tibial plateau, PF patellofemoral.
The main finding of this study is that the beneficial effect of autologous micro-fragmented adipose tissue as adjuvant for the treatment of diffuse degenerative chondral lesions is maintained in the mid-term. In addition, no complications were observed in the 3 year period showing the safety profile of this procedure. No patient, including the seven patients who received additional treatments, worsened compared to the pre-operative condition.
Despite the heterogeneity of the associated surgical procedures all the patients shared the presence of chondral lesions of different degrees of severity, which may have been responsible for the impairment in function and pain.
As reported in literature, articular surface damages, especially when diffused (three compartment OA), positively correlate with a decay in the outcomes in patients who received knee surgery for other reasons (Bonasia et al. 2014; Røtterud et al. 2012; Saithna et al. 2014; Su et al. 2018; Verdonk et al. 2016). Published data shows a decline in the clinical results in the mid to long-term for arthroscopic and chondral debridement procedures in cases of initial knee OA (Su et al. 2018). Some authors assessed the effectiveness of the arthroscopic or conservative treatments in patients diagnosed with knee OA (Kellgren-Lawrence grade 2 to 4) with 5 years of follow-up, concluding that arthroscopy provided no benefit in decreasing or delaying arthroplasty and that it can relieve symptoms only up to 2 years (Su et al. 2018). The same observation has been reported for ligament reconstruction, where the short and mid to long-term benefits are inferior in patients who have cartilage lesions. In a study of a cohort of ACL-injured patients with full-thickness cartilage lesions (ICRS grade III–IV), the authors showed that ACL-injured patients with full-thickness cartilage lesions reported worse outcomes and minor improvement after ACL reconstruction compared to patients without cartilage lesions at 2–5 years follow-up, although no significant differences between the two groups at the time of ACL reconstruction were present. This means that the observed differences between the groups must have occurred during the follow-up period (Røtterud et al. 2012). Furthermore, the outcomes of osteotomy procedures in patients with diffuse degenerative knee chondropathy worsen in the mid to long-term (Bonasia et al. 2014; Saithna et al. 2014). In a study reporting the results of a case series of opening wedge distal femoral varus osteotomies for valgus lateral knee OA, it is shown that re-operation for non-arthroplasty related surgery was common due, besides others, to infection and persistence of symptoms (Saithna et al. 2014). With regard to meniscectomy, in a recently published paper it is concluded that meniscus therapy including partial meniscectomy, meniscus suture, and meniscus replacement has proven beneficial effects in long-term studies in patients without cartilage damage, supporting the hypothesis that meniscectomy increases the risk of cartilage degeneration (Verdonk et al. 2016).
Based on the aforementioned published evidences, we should have expected, in the mid-term, a decay of the outcomes. Notably, the results have been maintained with no significant differences in all the evaluated parameters with respect to the 1 year follow-up assessment. Furthermore, in line with that already observed at 1 year, the patients with lesions in more than one compartment had higher and statistically significant improvements compared to patients with lesions in only one compartment (p < 0.01). This finding supports our hypothesis of using micro-fragmented adipose tissue for the treatment of the diffuse degenerative knee pathology as an adjuvant of the surgical procedures. Indeed, the maintenance of stable results at the last follow-up leads to hypothesize a protective role of micro-fragmented adipose tissue in a further chondral degeneration.
The seven patients who received additional biological therapies in the 3-year period, were young (mean age 36.3 ± 7.3 vs. 44.7 ± 11.4), very active in sport and 6 out of 7 had a patellofemoral chondropathy. Their conditions after 1 year did not worsen, but they probably needed an additional biological treatment because of their high functional demands and the presence of the patellofemoral chondropathy, which is a negative prognostic element, even if the small number of patients does not allow for any statistical correlation.
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Autologous mesenchymal stem cell application for cartilage defect in recurrent patellar dislocation: A case report
Recurrent patellar dislocation is a repeated dislocation that follows from an initial episode of minor trauma dislocation . Conservative management gives a minimal result in re-dislocation, with persistent symptoms of anterior knee pain, instability and activity limitation. Meanwhile, there is no gold standard treatment of realignment procedures. This can further cause cartilage lesion in the patella and femoral condyle, and consequently increase the risk of re-dislocation. Mesenchymal stem cells (MSCs) have been widely explored for treating cartilage defect due to their potency of chondrogenic differentiation. We present a novel approach of treating cartilage lesions in recurrent patellar dislocation by combining of arthroscopic microfracture and autologous bone marrow derived MSCs (BM-MSCs) after Fulkerson osteotomy.
Presentation of case.
A 21-year-old male presented with left knee discomfort. Ten years ago, the patient felt discomfort on the medial side of the knee and felt his knee cap slide out laterally. The patient experienced several episodes of instability ranging from a feeling of “giving away” until a prominent lateral sliding-off of his knee cap. Anterior knee pain has also occurred during activities such as climbing stairs or exercising.
Physical examination revealed slight pain on the anterior side of the patella, but no atrophy or squinting patella. Knee range of motion (ROM) was normal when the knee cap position was normal, but was limited when it was dislocated (0–20°). Lateral subluxation of the patella was found when the knee was extended from 90° flexion position (J-sign positive), positive patellar apprehension test, with medial patella elasticity/patellar glide >2 quadrants. The Q angle, in the 90° flexed knee position, was 10°, which was still normal. The plain radiograph imaging showed no abnormality. Insall-Salvati index was 1.12. The patient was diagnosed with recurrent patellar dislocation, with suspected cartilage lesion of the left knee.
The first surgery was an arthroscopy diagnostic and distal realignment procedure (lateral retinaculum release, percutaneous medial retinaculum plication, and antero-medialization of tibia tubercle/Fulkerson osteotomy). We found articular cartilagedefects on the lateral condyle of the femur with a diameter of 3 cm (Figure. 1A), and on the postero-medial with a diameter of 2.5 cm (Figure. 1B), and the depth of both was more than 50% of the cartilage thickness. We determined that the articular defect was Grade 3 according to International Cartilage Regeneration & Joint Preservation Society (ICRS). We performed a dissection of lateral retinaculum (lateral release) (Figure. 1C) using an electrocautery, continued by incising the medial side of tibia tuberosity and detaching the patellar tendon by using an oblique osteotomy procedure on tibia tuberosity, where the fragment slide 1 cm antero-medially and fixed with two 3.5 mm (length 40 mm) partial threaded cancellous screw, followed by percutaneous plication on the medial side of the patella using non-absorbable string (Figure. 2A). Post-operative ROM was 90° flexion without any dislocation (Figure. 2B) and the position of the screws was good (Figure. 2C).
Figure 1.A. Cartilage defect on the femoral lateral condyle with a diameter of 3 cm (pointed by the arrow). B. Articular cartilage defect on posteromedial patella with a diameter of 2.5 cm (pointed by the arrow). C. Lateral retinaculum dissection/lateral release using an electrocautery (pointed by the arrow).
Figure 2.A. Percutaenous medial plication using non-absorbable string no.2. B. Post-operative anteroposterior and lateral projection of plain radiograph imaging. C. Post-operative CT scan.
One month after surgery, full ROM and weight bearing exercises were started, including knee exercise until maximum flexion was reached along with quadriceps muscle exercise. Eighteen month after that surgery, we performed an iliac crestbone marrow aspiration; arthroscopic microfracture by using an awl until 4 mm depth was reached on the site located ±3–4 mm from the articular cartilage defect on the posteromedial patella and femoral lateral condyle (Fig. 3A); and tibial tuberosity screw removal.
Outcomes were assessed by using International Knee Documentation Committee (IKDC) score, visual analog scale (VAS) score and imaging. Baseline IKDC score was 52.9 and VAS score was 8. Nineteen months after the first surgery, IKDC score was improved to 93.1, while the VAS score decreased to 2. Six months after MSCs implantation, evaluation by MRI FSE cor T2-weighted signal (cartilage sequence) showed a significant growth of articular cartilage covering most of the defect (Figure. 4). Two years after the MSCs implantation, there was no complaint and full ROM was reached.
Recurrent patellar dislocation are uncommon problem, with recurrence rate 15%–44% after conservative management, while cartilage lesions following recurrent patellar dislocations are quite common, but still no gold standard or consensus on the management. This patient was diagnosed as chondromalacia Grade 3 Outerbridge classification and Grade 3 ICRS. One of the suitable procedures for recurrent patellar dislocation with chondromalacia, especially Grade 3 or 4, was Oblique Fulkerson-type osteotomy, with or without the release of lateral retinaculum. This distal realignment procedure could decrease patellofemoral pain by anteriorization of tibial tuberosity, decreasing articular contact pressure and at the same time medializing knee extensor mechanism. Therefore, we performed the Fulkerson-type osteotomy with lateral retinacular release, combined with percutaneous medial plication since the patient was already 21 years of age and the bone was expected to be mature so that the risk of premature physeal closure in proximal tibia can be avoided. This technique has demonstrated good results (86%), although it had a risk of tibial stress fracture in the healing process. The lateral retinacular release is an adjuvant after tibial tubercle medialization to re-center the patella. It was reported that isolated lateral retinacular release significantly gives an inferior long-term result compared to medial reefing. Percutaneous plication of medial patella procedure was indicated to build a strong construct by shortening the patellofemoral ligament, in order to prevent lateral sliding of the patella.
Treatment of articular cartilage defect remains challenging since it has limited self-healing capacity. Lesions that do not reach the subchondral zone will be unlikely to heal and usually progress to a cartilage degeneration. Limited blood supply in the cartilage and low chondrocyte metabolic activity disrupt natural healing that is supposed to fill the defect by increasing hyaline cartilage synthesis activity or stem cell mobilization from bone marrow to site of injury. The proper initial procedure for chondral lesion >4 cm2 was marrow stimulation by mosaicplasty or microfracture; and for a lesion <4 cm2 and >12 cm2 accompanied with symptoms, autologous cartilage implantation (ACI) beneath a sutured periosteal flap was promising. This procedure could not regenerate cartilage in the long term, due to loss of flap or cell suspensions. A scaffold (e.g. HA) was then used to act as an anchorage for chondrocytes adherence on cartilage defects and to promote the secretion of chondrocyte extracellular matrix. The BM-MSCs implantation could be an alternative source of the chondrocytes. Human BM-MSCs are relatively easy to isolate and to be cultured in such a condition that may retain their capability to differentiate into chondrocytes.
The MSCs effect was reported as effective as ACI and even had the advantage over ACI in terms of the number cells obtained, better proliferation capacity and less damage in the donor site. Treating large cartilage defects by using BM-MSCs showed good outcome, but the transplantation procedure was invasive. Wong et al. conducted a clinical study of the BM-MSCs intra-articular injection in combination with high tibial osteotomy (HTO) and microfracture for treating cartilage defect with varus knee. They reported that intra-articular MSCs injection improved the outcomes in the patients undergoing HTO and microfracture. Here we performed also a less invasive approach by injecting the autologous BM-MSCs intra-articularly, following the arthroscopic microfracture using an awl to penetrate the subchondral bone plate in the cartilage defects, which led to clot formation. This clot contains progenitor cells, cytokines, growth factors and pluripotent, marrow-derived mesenchymal stem cells, which produce a fibrocartilage repair with varying amounts of type-II collagen content. Cytokine within the fibrin clot will attract the injectable stem cells to the cartilage lesions.
The HA injection in this patient was aimed to suspend the MSCs and to support regenerative potency of MSCs with chondroinductive and chondroprotective potency of HA. Intraarticular injection of MSCs suspended in HA could be an alternative treatment for large cartilage defect. Supporting microfracture technique by intra-articular HA injections had a positive effect on the repair tissue formation within the chondral defect. The MRI showed that there was a growth of articular cartilage covering most of the defect even though it was not perfect as yet.
This case report demonstrated that combining Fulkerson osteotomy with the lateral retinacular release and percutaneous medial plication was effective in treating chronic patellar instability. The combination of microfracture and MSCs implantation was safe and could regenerate the articular cartilage in this patient.