Perineural local anesthetic treatments for osteoarthritic pain

Abstract

The most common disabling symptom of osteoarthritis (OA) is pain. Clinical investigations using disease-specific animal models have increased our insights into the pathophysiology of osteoarthritic pain. As the prevalence of OA continues to rise and current available treatment options give less than optimal levels of pain relief, opportunities to develop treatments to address osteoarthritic pain are increasing. Targeted administration of local anesthetics along sensory/motor nerves can provide an alternative strategy for managing osteoarthritic pain. Moreover, the development of engineered therapeutic drug delivery systems may allow for sustained perineural delivery of local anesthetics as opposed to the traditional intraarticular joint injections. This review presents an overview of 1) the pathophysiology of persistent pain associated with OA of the hip, shoulder, and knee and 2) the emerging therapeutic role of local anesthetics in providing analgesia for joint-related pain symptoms.

Lay Summary

Osteoarthritic pain is one of the most common reasons patients seek medical attention. However, common oral analgesic treatments are fraught with several clinical challenges including off-target side-effects, addiction, and short duration of analgesic efficacy. Direct delivery of local anesthetics to the perineural space surrounding peripheral neurons are proving to be forthcoming clinical approach that may be superior to traditional analgesic approaches. This review describes current diagnostic and therapeutic approaches for osteoarthritis pain and the clinical data regarding local anesthetic injections for shoulder, hip, and knee joint pain. Furthermore, this review describes the future directions for clinical use of ultrasound-guidance for focal drug delivery and biomaterial drug delivery systems for sustained drug release which both may provide further advancements for analgesic treatments of osteoarthritis pain.

INTRODUCTION

Osteoarthritis is the most prevalent arthritic condition and cause of joint-related pain and disability among older adults [2]. Advanced age is a primary risk factor for developing OA therefore, as the average age among adults increases so does the occurrence of osteoarthritis [3]. Over the past two decades the number of patients clinically diagnosed with arthritic condition has steadily increased from 18.7% of the adult population in 1997 to 21.5% in 2003 and estimations suggest upwards of 25% of the adult population will have a diagnosis by 2030 [4]. The increasing prevlance of OA also creates a significant economic toll of more than $322 billion a year including direct medical costs and indirect medical care costs as well as loss of productively [5]. Increasing demand for medical interventions that can effectively treat OA which result in surgical replacement of joints which lays burden on the patient, the medical field, and the caregivers of patients post-operatively. Therefore, identifying adequate analgesic treatments are necessary to meet these critical clinical and economic needs.

A hallmark characteristic of osteoarthritis is the progressive loss of articular cartilage which can occur over several years of decades, potentially leading to whole joint organ collapse [2, 6–10]. The degrees of osteoarthritis disease severity are defined by bone spur formation, pain and joint stiffness, inflammation, cartilage erosion, and subchondral bone remodeling (i.e., sclerosis and/or cysts) [6–8]. Although, OA is clinically defined by joint damage, joint-related pain is the primary driver in the decision to pursue medical attention [11, 12]. It is believed that during the early stages of the disease, symptoms are more localized, predictable and often triggered by specific activities or strenuous movements and as the disease develops, pain symptoms can intensify, become less predictable and may occur with lower impact activities, after long periods of sitting, or at certain times of day (i.e., morning stiffness or night pain) [10, 13–15].

While pain can be present at any stage of the disease, the severity and intensity of pain symptoms may increase as the disease develops because of the pathophysiology of osteoarthritis but also from potential comorbidities that occur with advancing age [10, 16, 17]. Patients in primary care with osteoarthritis report that osteoarthritis is an “evitable” aspect to aging [18] with patient perceptions of disease-related disability being higher among patients diagnosed with osteoarthritis compared to patients that have other common age-related diseases including, hypertension, diabetes, or heart disease [19]. Eighty percent of osteoarthritic patients report that their symptoms limit their overall mobility and an additional twenty-five percent of patients report that their symptoms significantly impact their ability to conduct daily activities [20]. In a study assessing the occurrence of daily pain in patients diagnosed with knee osteoarthritis, 78% of participants reported they experienced a daily pain flare or episode, usually described as being “sharp”, over a 7-day at-home study and 24% reported flares about 50% of the time [21]. While there are no available therapies that can halt or slow the progression of osteoarthritis, the major clinical goals of treating OA are to provide pain relief, attenuate the progression of joint degeneration, and restore joint function [22].

Total joint replacement is a last resort option for the treatment of severe OA symptoms. Inadequate pain relief from osteopathic joints and functional limitations are the leading drivers in the decision for total joint replacement [23]. More than 900,000 people undergo hip and knee surgery every year in the United States to treat symptoms. More than 53,000 people in the US have prosthetic total shoulder replacement. Total joint arthroplasty is the surgical addition of a replacement weight bearing surface within the joint cavity. Prior to placement of the device, orthopedic surgeons can smooth rough bony edges to prevent further irritation and pain. The replacement joint is then inserted to better support the weight between your bones to alleviate knee pain associated with meniscus tears, cartilage defects, and ligament tears. However, the presence of the device within the joint may interfere with the analgesic efficacy of medications administered postoperatively to alleviate pain [24]. While, long-term postoperative studies following knee arthroplasty show high rates of survivorship, positive effects on weight loss, functional improvement (e.g., using the stairs), and is a widely accepted method for treating advanced stages of OA [25] surgical joint replacement does not necessarily improve pain symptoms [26, 27]. Several studies assessing post-operative pain revealed that approximately 9% and 20% of patients that underwent hip and knee surgery, respectively developed unfavorable pain within three months to five years [28]. Inadequate management of post-surgical pain can increase a patient’s risk for developing chronic pain, physical disability, decrease their ability to engage in physical therapy programs and their overall satisfaction with the therapeutic outcomes of surgical intervention. We currently do not understand why pain persists following surgery, it is likely due to a composite of both biological (e.g., physical trauma) and psychological factors (e.g., pessimism) caused by surgical intervention and recovery [25]. One study showed that pre-surgical multidisciplinary informational sessions that described to patients the details of the surgical intervention and what patients should expect during the procedure showed less anxiety and pain following total hip-replacement surgery compared to patients that received the standard information [29]. Even so, to provide adequate pain relief for patients suffering from joint degeneration, current clinical therapies need to be effective with minimal risk for worsening symptoms.

Other pain interventions commonly employed to manage osteoarthritis symptoms include, physiotherapy, anti-inflammatory analgesics, corticosteroid injections, and hyaluronic acid injections. Minimally invasive injectable therapies and viscosupplements are gaining attention as alternatives to oral medications due to their improved safety and efficacy [30, 31]. Biological therapies such as platelet rich plasma, and stem cell therapy aim to support cartilage regeneration for OA patients and are also emerging or experimental therapies that may be used to treat joint pain [32, 33]. However, peripheral nerve blocks by way of local anesthetics are emerging as another promising non-invasive therapeutic strategy to manage pain [34, 35]. Moreover, engineered approaches that locally deliver anesthetics may both sustain analgesia and increase the efficacy of current clinical uses of local anesthetic injections for orthopedic medicine. With advances in ultrasound guidance, visualization of soft tissue provides more opportunities for perineural drug delivery of local anesthetics as a cutting-edge clinical approach for targeting specific nerves that contribute to joint-related pain. Perineural injections of analgesics if effective can provide direct benefit by targeting adjacent peripheral nerves that contribute to pathological pain symptoms while also indirectly supporting a patient’s ability to attend rehabilitation or physiotherapy to improve joint function, movement, and flexibility. The focus of this review is to provide a comprehensive review of how osteoarthritic pain is clinically assessed, the anatomical innervation of common joints affected by osteoarthritis, the use of perineural injections for osteoarthritic pain, and finally a section discussing the future directions that may improve current paradigms for long term pain relief.

DIAGNOSING OA PAIN

Diagnostic Joint Imaging

The advancement of OA disease is defined by the presence of osteophytes, the narrowing of joint spaces, sclerosis, cysts, and physical deformity [6–8]. Patients diagnosed with one or more of these pathological features are categorized as having radiographic OA. Patients may also present with classical symptoms such as, joint tenderness, stiffness, reduced range of motion, as well as pain and are classified as having symptomatic osteoarthritis. Patients that present with pain, stiffness, and discomfort in the same joint that also has radiographic evidence of osteoarthritis are categorized as having ‘symptomatic’ or ‘symptomatic radiographic’ OA.

Assessing and monitoring osteoarthritic joints requires several imaging techniques [36, 37]. Over the past several decades, the reference standard for defining knee OA is by the Kellgren-Lawrence (K/L) radiographic grading scheme and atlas [38]. This scoring paradigm defines knee OA in 5 levels (level 0–4). These levels are defined by several parameters including the presence of osteophytes, the narrowing of joint spaces, sclerosis, cysts, and physical deformity [6] (Figure 1–3). Other metrics may also be used which allow for more semi-quantitative examination of individual patient pathology such as assessing the inter-bone distance to measure joint space width (JSW) in the knees and hips [7, 8].

Fig. 1. Radiographic X-Ray images of mild and severe osteoarthritis of the hip.

(a) Mild changes description: Anterior-Posterior (AP) of the pelvis and crosstable lateral views show the well-maintained hip joint space. There are small marginal osteophytes. (b) Severe changes description: AP views of the left hip. There is marked deformity of the left femoral head and likely some degree of avascular necrosis. There is associated deformity of the acetabulum and narrowing of the superior lateral aspect acetabulum with sclerosis on the acetabular edge. Arrows denote physical changes within the joint.

Fig. 3. Radiographic X-Ray images of mild and severe osteoarthritis of the shoulder.

(a) Anterior-Posterior internal rotation views of the right shoulder showing no evidence of a fracture or dislocation. There are no calcifications seen in the rotator cuff. There is some minimal irregularity along the superior lateral aspect humeral head. Otherwise, no significant bony, joint space or soft tissue abnormalities are identified. (b & c) Anterior-Posterior and Axillary views of the right shoulder with severe osteoarthritis. Complete obliteration of the glenohumeral joint space with evidence of erosive type of osteoarthritis. Arrows denote physical changes within the joint.

While radiographs are commonly used to evaluate joint health, when used alone, radiographic imaging can only indirectly imply degeneration of cartilage through the assessment of joint space narrowing (JSN). However, as found in a study by Amin et al., one-fifth of patients that did not show radiographic evidence of JSN did show cartilaginous degeneration revealed by magnetic resonance imaging [1] [39]. One of the symptoms of osteoarthritis that has been shown to be highly correlated with pain and disease progression is synovial inflammation or synovitis [40]. Within the osteoarthritic joint, elevated levels of inflammatory factors and increased mechanical stress can cause joint stiffness and pain. Inflammatory pain may be reported as feeling “sharp” and localized to a specific bodily region [13]. Synovitis can cause degeneration of articular cartilage and subsequent structural changes that occur within an osteoarthritic joint. MRI can provide quantitative insight to structural changes that would be otherwise not revealed with traditional radiographic imaging. In addition, optical coherence tomography (OCT) and ultrasound (US) can also be used to evaluate soft tissue changes as well as inflammation [37]. To identify joints that may be at risk for degeneration before the disease progresses to more advanced stages, with irreversible structural damage, visualizing and assessing the whole joint organ health is necessary.

While imaging techniques guide more than 85% of pain management strategies, similar degrees of osteoarthritis disease severity among patients does not necessarily correlate with levels of self-reported pain [6, 38, 41–43]. In the 1987 Framington heart study cohort, radiographs from 1,424 participants ages 63–94 were assessed for a population-based study of symptomatic knee osteoarthritis. Although no significant differences with regards to the prevalence of radiographic knee OA were detected between men and women, female participants in the study were more likely to have symptomatic knee OA [44]. The Mayo clinic reported similar findings from their population study of Rochester, Minnesota residents that osteoarthritis of the knee affects men and women similarly however, female residents were more likely to present with symptomatic hip OA [17]. Differences in gender could be related to psychosocial differences between male and female patients with reporting pain (i.e. male participants may downplay pain symptoms)[45]. In another classic study, 3,018 residents of Johnston County, North Carolina were assessed for prevalence of knee OA [46]. The study confirmed that the prevalence of OA increased with age and additionally, that female participants or participants that identified as being African American were more likely to report knee symptoms [46]. The Johnston County Osteoarthritis project was novel in that it assessed ethnic as well as gender and age-related factors with regards to prevalence of OA, disease severity, and the presence of symptoms compared to straight radiographic evidence [46]. This is important because the relationship between osteoarthritis and symptomology is not necessarily correlated; different populations with higher risk of developing OA should be considered carefully in that their joint pathology may not correlate with their symptoms [47, 48]. Therefore, clinical strategies that can effectively manage pain symptoms regardless of radiographic pathology is necessary to provide adequate clinical care of patients.

Clinical scoring of pain and joint function

Clinical assessment of pain is essential for establishing a safe and effective method for managing symptoms. A basic verbal assessment of a patient’s symptoms such as the patient’s pain including intensity or severity of pain, does the pain radiate, what are triggers that exacerbate pain or relieve pain, how did the patient previously respond to analgesics or other interventions for pain management, and are there physical or psychological associated symptoms, can help guide treatment. Semi-quantitative clinical assessments include patient self-report that attempts to quantify symptoms by asking patients to rate their pain intensity using verbal rating scales, numeric rating scales, and/or visual analog scales. The Verbal Rating Scales (VRS) prompts individuals to describe their pain intensity and duration by responding to a series of statements that aim to describe the pain experience. Each statement is followed by a scale which typically consists of a categorical list of descriptors ranging from “never” to “always”, spanning as few as four possible answers to choose from or as many as fifteen possible descriptors [49]. Some limitations of VRS include limitations of the number of possible descriptors as well as variability in patient interpretation and responses to the descriptors based on patient differences in overall vocabulary (i.e. children or less mental competent), education level, sex, cultural or ethnic factors which can lead to an overestimation or underestimation of pain symptoms [49]. Despite this, the VRS is considered useful because the score is easily administered across multiple settings. Bech and colleagues showed that elderly patients, regardless of level of cognitive impairment, measured by the short Orientation-Memory-Concentration Test, demonstrated overall adequate competency at describing their levels of pain following hip fracture surgery [50]. VRS can be also used in tandem with other scoring systems. Since verbal rating does not give a measurement between descriptors along the scale, comparing VRS results with a scale with definable intervals may be used to confirm symptom severity such as the Visual Analog Score. The Visual Analog Score (VAS) system is comprised of a spectrum of pain intensities plotted along a straight line, starting with “no pain” and ending with “worst pain imaginable” [51]. The patient marks their level of pain intensity along the line between the two fixed points. Other versions such as Graphic Rating Scales display additional points between the two endpoints which are labeled with descriptors or numerals to declare specific levels of intensity. Finally, the Numeric Rating Score (NRS) is a similar system to VAS however, numbers are used to describe pain intensity [51]. The NRS scale can vary in the total number of possible answers (e.g., 0–10, 0–20, or 0–100) allowing more distinctive numerical description compared to a predetermined scale with 5 descriptors. This method can also be used when an in-person patient assessment is not possible.

The most common clinical tool for evaluating Hip and Knee Osteoarthritis is the Western Ontario and McMaster Universities Arthritis Index (WOMAC). The self-administered questionnaire assesses three components, pain, joint stiffness and physical function using a numerical scale with about four possible answers. While the functional component of the test has been shown to be consistent across patients, the pain and stiffness sections can be variable across test-retest scores. The WOMAC index is a common tool used in clinical trials and thus, improving this tool is a topic of review among the American Academy of Orthopedic Surgeons (AAOS). In 2017, the AAOS declared a new clinical tool to assess osteoarthritic pain and joint function within the upper and lower extremities [52]. The questionnaire is comprised of statements that inquire about quality of life, as well as includes standardized joint assessments and joint-specific disability indices. In summary, taking both the pathophysiological components of osteoarthritis as well as the patient’s experience of pain are essential for the treatment of osteoarthritic pain.

JOINT INNERVATION

Pain is “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [53]. As a result of actual or potential tissue damage, pain is produced by a complex coordination of neural circuitry that is derived from the somatosensory system [54]. The somatosensory system is comprised of excitable cells, called nociceptors, which encode noxious stimuli, referred to as nociception. Nociceptors have a bifurcating axon that projects peripherally to sense the micro-environment of tissues as well as projects centrally to the spinal cord and later, high-order cognitive centers for the perception of pain. In peripheral tissues, the axons and free nerve terminals of nociceptors comprise a variety of ion channels and protein receptors that respond to the pathophysiological cellular functions involved in tissue damage or disease pathology. Under non-pathological conditions, nociceptive neurons that supply the joints are typically not stimulated during normal physical movement, such as those that occur within the physiological joint range of motion like flexion or rotation, nor with mechanical stimulation (e.g., pressure). However, during pathological conditions, such as osteoarthritis, neuroactive factors released from surrounding cells, immune cells, and the extracellular environment activate ligand-gated protein receptors and voltage gated ion channels expressed on the cell membrane of nociceptors [6, 55, 56]. Pain that results from this mechanism is referred to as nociceptive pain. Nociceptive pain can arise from actual or potential damage to non-neural tissue and is typically the result of peripheral nociceptor stimulation by factors released during tissue damage [57]. With nociceptive pain, the time course is generally self-limiting, and the precipitating cause is usually known. In comparison, during more advanced stages of osteoarthritis adaptive changes within the sclerotome and connective tissue, such as the loss of articular cartilage and subchondral bone remodeling, can subsequently irritate or damage nearby nerves which can manifest as neuropathic pain. Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Where in central neuropathic pain is caused by a lesion or disease of the central somatosensory nervous system, peripheral neuropathic pain is pain caused by a lesion or disease of the peripheral somatosensory nervous system.

Clinically, neuropathic pain is differentiated from nociceptive pain by the presentation of hyperalgesia and/or allodynia. Hyperalgesia is increased pain from a stimulus that normally provokes pain which reflects increased pain on suprathreshold level [54]. Allodynia is pain due to a stimulus that does not normally provoke pain. Both pain phenotypes are indicative of physiological changes in the sensory nerve’s response and/or threshold to a given stimuli. A patient with neuropathic pain may also report paresthesia and/or dysesthesia which can include burning, “electric shock-like”, or abnormal sensations [10, 58]. These sensations can be evoked by certain stimuli (i.e., light touch, pressure of clothing, wind, sitting, or temperature) or spontaneously occur (i.e., night pain). Patients may report numbness, indicating a loss of neuronal function. Both nociceptive and neuropathic pain can occur simultaneously, therefore potentially increasing the intensity and chronicity of symptoms [59].

The mechanisms that contribute to the generation and persistence of osteoarthritic pain are complex and are likely a composite of more than biological mechanism. Moreover, mechanisms involved in the persistence and intensity of joint related pain may include both the peripheral and central nervous systems [10]. Continuous stimulation of peripheral nociceptors can alter the expression of genes and subsequent protein expression which can ultimately alter neuronal activity or sensitivity to stimulation (i.e., hypersensitivity or allodynia). For instance, altered expression of ion channels and protein receptors that are expressed in the neuronal cell membrane can have profound physiological effects on afferent sensitivity [60–62]. Altered expression of voltage gated sodium channels, voltage gated potassium, and calcium channels can alter the activation thresholds for eliciting action potentials (i.e., sensitization) [54, 63]. Reduced activation thresholds can facilitate long-lasting excitation eventually shifting the stimulation threshold also known as sensitization of the peripheral or central nervous systems [54, 63, 64]. Both phenomena can contribute to transition from acute adaptive pain to chronic maladaptive pain [64, 65]. Preventing the persistence of peripheral sensitization and the subsequent central changes can possibly decrease the intensity and chronicity of the pain experience [54].

Understanding how joints are innervated is important for determining neural sources of joint-related or musculoskeletal pain which can ultimately help guide local pain treatment [66–69]. Clinicians conventionally use physical examination of muscular and skin tissues near the targeted tissue to assess potential neural contributors of joint or musculoskeletal hypersensitivity. Palpation of the skin and muscles, ultrasound of surrounding tissues, or imaging studies of joint tissues can help identify neuronal origins of pain symptoms [70, 71]. Compared to other tissues in the body, such as cornea and skin, muscles and joints are less densely innervated. Anatomical classification of which nerves supply which joint tissues is ongoing however, currently it is believed that articular branches of one or more individual spinal nerves innervate any given joint organ [72, 73].

Humans have 31 pairs of spinal nerves that supply sensory and motor nerve fibers to the four segments of the human body, cervical, thoracic, lumbar, and sacral. Articular branches of spinal nerves have been documented at the levels of the fibrous capsule, ligaments, adipose tissue, menisci, as well as the synovial layer of the joint organ. Moreover, the neurons that supply a given joint may also supply proximal cutaneous and muscular tissues, referred to as Hilton’s Law [72]#32;Hilton, 1896 #33]. Therefore, the underlying disease pathology may affect multiple tissues through specific spinal nerves resulting in muscular, cutaneous, as well as joint-related pain. In short, identifying specific peripheral neuronal contributors of joint-related symptoms may help guide the delivery of analgesic molecules that can alleviate cross-tissue sensitivity. Although our current understanding of how articular tissues are innervated is far from complete, the next section will explain some of the findings from anatomical studies that have attempted to close this gap in knowledge to enhance our ability to interpret experimental and clinical determinants of joint-related pain. Here, the current knowledge regarding the innervation of joints commonly reported among osteoarthritic patients: the shoulder, hip, and knee are discussed.

Shoulder Innervation

Compared to all the joints in the body, the shoulder has the greatest range of motion. The muscular architecture of the shoulder joint allows for complex movements whereby compromised shoulder movement due to pain, weakness, and stiffness can impede daily activities (personal hygiene, eating, dressing, work, etc.) and result in physical disability therefore, significantly affecting the quality of life of otherwise, healthy individuals [74, 75]. Shoulder pain is the third leading cause of medical consultation with primary care physicians for musculoskeletal pain [76]. Approximately 1% of the adult population seeks medical attention for new shoulder pain every year [77]. Diagnosing shoulder pain includes determining whether the pain is localized to one or more of the joints that comprise of the shoulder, neck, rotator cuff, or other tissues proximal to the shoulder girdle [78]. The shoulder girdle, also known as the pectoral girdle, connects the bones of the upper limbs, the clavicle, scapula, and coracoid, to the appendicular skeleton [79]. Within the pectoral girdle the sternoclavicular (SC), acromioclavicular (AC), and the glenohumeral joints (GH) coordinate the movement of the shoulder and upper limbs. The SC joint is a synovial, saddle-like, ball and socket joint that connects the sternal end of the clavicle, the manubrium or breastbone, and the costal cartilage of the first set of ribs. The SC joint allows movement of the pectoral girdle and upper limbs. The AC joint is a synovial joint that supports gliding shoulder movement, and the GH joint is a ball and socket synovial joint which supports the widest range of shoulder movements. The AC joint and GH joint make up the traditional shoulder and are commonly diagnosed with osteoarthritis [76].

Comprehensive studies of the shoulder joint led to the observation that the spinal segmental innervation of the shoulder is regionally specific not joint specific. The peripheral nerves that supply joints, muscles, and skin that comprise the shoulder mostly originate from the cervical and upper thoracic spinal segments (C3 to T1) (56). The brachial plexus supplies the majority of cutaneous tissue of the upper limbs (Figure 4) [79]. Spinal nerves C5-T1 create the cervical plexus which supplies the cutaneous shoulder tissues. The supraclavicular nerves emerge from the anterior C3 and C4 spinal nerves to supply the skin closest to the clavicle and the pectoralis major muscle [72, 80, 81].

Fig. 4.

Peripheral nerve supply of brachial plexus adapted from Barash et al., 2013 [166]

There is variability in exactly which spinal nerves innervate which articular component [66, 68]. Gardner and colleagues observed that an articular branch of the axillary nerve innervates the inferior region of the shoulder in adult shoulder tissues [68]. Additional observations of small nerve bundles that branch from the axillary nerve and posterior cord of the brachial plexus enters the inferior and anteroinferior regions of the shoulder and terminate at the fibrous capsule [68]. The SC joint is supplied by the suprascapular nerve and subclavian nerves, a small nerve branch from the brachial plexus formed by the union of C5 and C6 spinal nerves. Pain in this joint can be felt by pushing on the SC joint. In comparison, the AC joint encapsulates the point of the shoulder, also known as the acromion, and the clavicle and is supplied by the suprascapular nerve, lateral pectoral and axillary nerves [79]. The GH joint is also thought to receive neural innervation from the axillary nerve as well as radial nerve [68, 82].

In osteoarthritis, increased synovial inflammation or synovitis’s can cause the fibrous capsule encapsulating the joints to stiffen. Increased stiffness can cause muscle contraction thereby, reducing the shoulder’s range of motion. The gross anatomical innervation of the shoulder joint capsule was first classified by Nikolaus Rüdinger in 1857 [83]. The capsule refers to the ligament that encapsulates and stabilizes the joint. During the original assessments of the shoulder, two major nerves, the axillary and suprascapular nerves, were identified as the chief neural supplies of the shoulder capsule (Figure 5). Anatomical and tracing studies of adult human shoulders increased our understanding of the neural supplies of the shoulder capsule including articular branches from the posterior cord of the brachial plexus, axillary, subscapular and suprascapular nerves, the lateral anterior thoracic nerve and in some cases the radial nerve and sympathetic nerve fibers [66, 68, 84, 85]. The posterior cord descends along the subscapularis muscle, which covers the anterior capsule of the shoulder-joint, enters the anterior region of the joint, and supplies the fibrous layer but may also reach the synovial layer [68]. This same region of the shoulder joint is also supplied by articular branches of the suprascapular and anterior thoracic nerve fibers [68, 83].

Fig. 5. Image representing shoulder innervation from Gardner and colleagues [68].

The Axillary and Suprascapular nerves innervating the anterior and posterior shoulder tissues, respectively.

In short, the suprascapular, axillary, and subclavian, and pectoral nerves are major supplies of shoulder innervation and may be targeted to alleviate pain associated with the shoulder joints. Local delivery of nerve blocks that target neuronal supplies of skin, joint, or muscles associated with painful OA joints may be used in combination with physiotherapy to help patients improve their shoulder range of motion and load bearing for functional utility. However, nerve blocks may not be suitable for patients with more advanced stages of OA or following arthroplasty as the absence of pain may contribute to physical injury (e.g., falling) which can impede functional long-term recovery [86].

Hip Innervation

The hip joint provides stability for a wide range of movements including gliding and abduction. The femurs are connected to the vertebral column by the pelvic girdle which is comprised of a ring of bones [79]. A strong pelvic girdle supports the transfer of weight of the upper body from the axial region to the lower appendicular skeleton and is joined by the lumbosacral and sacrococcygeal joints. The trunk and lower limbs are connected by the sacroiliac and pubic symphysis joints. The sacroiliac joints differ from most of the other bodily joints because it has limited mobility and instead functions to transfer most of the upper body weight to the hip bones [79]. The right and left hip bones are connected by strong anterior synovial joints and posterior syndesmosis. The nerves that supply the hip joints are the femoral nerve, obturator nerve, sciatic nerve, and the superior gluteal nerve.

The anterior section of the hip joint capsule is supplied by the articular branches of the femoral nerve and the obturator nerve (Figure 6). The femoral nerve is responsible for the sensory innervation of the anterior and anterolateral region of the hip joint capsule. One of the two articular branches of the femoral nerve supplies the iliopsoas muscle. A side branch “passe vertical” from the femoral nerve innervates the anterior side of the hip joint capsule. The other articular branch of the femoral nerve passes at a lateral angle right across the iliopsoas muscle and joins the lateral margin of the hip joint capsule. The femoral nerve was also observed to have an accessory nerve, also referred to as an accessory femoral nerve, that was responsible for the sensory innervation of the anterior region [87]. The anteromedial portion of the hip joint capsule is supplied by articular branches of the obturator nerve. These branches may derive from the anterior branch, the posterior branch or the trunk of the obturator nerve. One branch of the obturator nerve passes posterolaterally and innervates the hip joint capsule. The posterior branch, passing over the external obturator muscle and runs between the adductor brevis and magnus, comes from the trunk of the obturator nerve [87].

Fig. 6.

Representation of neuronal supply of the hip image from Parvizi and colleagues [167]

The posteromedial section of the hip joint capsule is supplied by articular branches from the sciatic nerve, and nerves to the quadratus femoris. The nerve to quadratus femoris muscle with the articular branch for the hip joint passes out of the sciatic nerve immediately after penetration through the infrapiriformis foramen. At the same level, an articular branch from the sciatic nerve exits through the lesser sciatic notch below the sacrotuberous ligament and innervates the internal obturator muscle. There is a split into two articular branches; one passes posteroinferiorly, and the other posterolateral. The nerve to quadratus femoris muscle innervates the posteroinferior section of the hip joint capsule. The superior gluteal nerve innervates the posterolateral capsule of the hip joint. In one study, an articular branch from the sciatic nerve was also recorded to supply the posterosuperior region of the hip joint capsule [87]. The posterior section of the hip joint capsule is supplied by the articular branches from the nerve to quadratus femoris muscle, as well as by articular branches from the superior gluteal nerve and directly by the sciatic nerve [87].

In summary, branches of the femoral nerve, obturator nerve, sciatic nerve, and superior gluteal nerve may be useful for identifying neuronal contributors of hip OA pain. The hip has several joints that comprise the pelvic girdle.

Knee Innervation

The lifetime risk of developing symptomatic knee OA is approximately 45% for males and females at normal or underweight but the risk increases to 60% for patients with high body mass indexes [88]. Approximately half of the affected US population has knee pain of which 50% of patients report severe and disabling symptoms [89, 90]. The knee is comprised of three bones the femur, tibia, and patella which form the knee or tibiofemoral joint. The knee joint is a major component of structural support and weight bearing for the body. The first comprehensive studies of the knee’s articular neurology focused on the innervation pattern of the feline knee joint [91] of which the posterior articular nerve of the posterior tibial nerve were identified as neuronal contributors of the lateral and medial regions of the posterior knee joint capsule [91]. The medial articular nerve which stems from the antero-medial region of the feline thigh and from the parent saphenous nerve. In more recent studies, immunohistochemical techniques using antibody-based approaches helped describe the nociceptive fibers that innervate the human knee [92]. The human knee joint was originally described to include branches from the femoral, sciatic, obturator and saphenous nerve [67, 92] (Figure 7). Surrounding ligaments and capsule are supplied by articular branches from the femoral tibial and common fibular nerves as well as obturator nerve.

Fig. 7. Illustration representing the innervation of the knee from Goldman and colleagues [31].

a) Anterior-posterior illustration of the knee, b) lateral illustration of the knee and c) posterior-anterior illustration of the nerve supply to the knee.

The tibial nerve branches form the superior and inferior medial genicular nerves whereas the common peroneal supply the superior lateral and inferior lateral genicular nerves. The femoral nerve is the largest branch of the lumbar plexus. Terminal cutaneous branches of the femoral nerve and saphenous nerve innervates the thigh and the innervation of the knee. The branches of the peroneal, saphenous, tibial, and obturator nerves that surrounding the knee are called the genicular nerves (Figure 7). The tibial nerve branches form the superior and inferior medial genicular nerves and a third branch supplies the popliteal fossa [93, 94]. The common peroneal becomes the superior lateral and inferior lateral genicular nerves. The lateral superior genicular nerve has been found to originate from the common peroneal part of the sciatic nerve, superior to the joint [95]. Moving down the leg, the lateral superior genicular nerve supplies the superolateral side of the knee capsule and innervates the biceps femoris muscle and the iliotibial muscle. The genicular nerves also supply the distal femur, meniscus and patella. Using ultrasound, identifying anatomical landmarks such as the superior lateral, superior medial, and inferior medial genicular arteries can help guide perineural injection therapy or radioablation to decrease nociception and subsequent pain caused by the genicular nerves [34, 96].

Clinically utilizing Hilton’s law, analgesic medication applied to the cutaneous sensory nerves of the shoulder, such as the suprascapular nerve, can alleviate peripheral neuropathic pain associated with the shoulder joint capsule. Combining these treatment approaches with local administration of molecules that reduce nociception could be an effective approach for reducing osteoarthrosis pain.

PERINEURAL INJECTION THERAPY FOR OA PAIN

Understanding the neural contributors of patient specific joint-related pain may help guide clinical pain treatment in that determining active neural contributors to a patient’s pain, clinicians can locally administer a nerve block to prevent neurotransmission of painful stimulation for the physical betterment of joint function. To help guide perineural injections of local anesthetics, nerve stimulation may be used to detect muscle-nerve relationships. During nerve stimulation electrical impulses are delivered across the skin which can cause muscle twitching. Identifying muscle-nerve relationships can guide where best to deliver the drug however, this method alone limits the bodily regions that can be administered blinded without additional support with radiographic or ultrasound. While fluoroscopy has been commonly used to help guide perineural injections, ultrasound guidance is increasing in popularity in the clinical setting impart due to its accuracy of visualizing soft tissue and vasculature but is also less expensive and has no associated ionizing radiation exposure [97]. Once the location for injection is confirmed with or without imaging guidance, a few milliliters of the anesthetic drug are injected into the perineural space to assess possible toxicity from the injection before the remaining analgesic solution in administered. The next section will review the clinical literature on the current perineural injection therapies including local anesthetic blocks for treating osteoarthritis pain associated with the shoulder, hip, and knee for both nonsurgical and surgical pain.

LOCAL ANESTHETICS

Local anesthetics are widely used in orthopedic applications for clinical diagnosis of chronic pain conditions as well as to facilitate pain relief [98, 99]. Local anesthetics may be used as neuraxial anesthesia during orthopedic procedures (i.e. total joint replacement) to block nerve transduction or to facilitate pain relief postoperatively or for nonsurgical conditions [99, 100]. Prior to clinical assessment patients may also receive a low dose, local anesthetic injection administered near the joint space to determine the contribution of articular nerves to symptoms or to provide pain relief for clinical assessments that may be otherwise painful [100, 101].

Common long-acting anesthetics that are used to prolong sensory or motor block include the bupivacaine, ropivacaine, and levobupivacaine [102]. Their chemical structure has three basic components, a hydrophilic amine end, a lipophilic aromatic end, and a linkage connecting the two (Figure 8). Their three-dimensional structure also allows they have chirality with two enantiomers that can exist in different spatial confirmations. These enantiomers are described by their optical reaction to polarized light, the enantiomer that spins in the dextrorotatory or clockwise direction is referred to as R(+)enantiomer or in the levorotary or counterclockwise is labeled S(−)enantiomer. While both enantiomers have similar physiochemical properties, they can have vast physiological effects including different in affinities for ion channels permeant for sodium, potassium, or calcium as well as toxicology profiles [103, 104]. Toxicity of the nervous system and cardiovascular is less with exposure to the S(−)enantiomer compared to the R(+)enantiomer [104].

Fig. 8.

Chemical structures of common local anesthetics

Unlike charged ions like sodium that require a channel to cross the plasma membrane, local anesthetics are amphipathic and act as weak bases that can passively cross the plasma membrane. Within the neuron, local anesthetics reversibly bind to an amino acid reside within the inner pore of voltage-gated sodium channels (Nav1.1–1.9), in peripheral afferents, nociceptors specifically express subtypes Nav1.7-Nav1.9. The binding of local anesthetics occurs when the protein channel undergoes confirmational changes during membrane polarization at the open or inactive states. By doing so, LAs prevent the flow of sodium ions and thus, subsequent membrane depolarization and action potential generation. Their effectiveness at blocking peripheral neuro-transduction is dependent on their chemical structure and lipid solubility such that, increased lipid solubility allows the local anesthetics to diffuse more easily across peripheral nerve sheaths and further, individual neuronal membranes. Compared to ropivacaine, bupivacaine and levobupivacaine are more lipid soluble and thus more potent [105] however, bupivacaine has more reported global toxicity affecting the cardiovascular system, peripheral nervous system, and muscle tissue [106–108]. Ropivacaine is comparably less potent compared to bupivacaine, but not necessarily less effective and patient reports suggest faster motor nerve recovery [109].

Compared to systemic administration (e.g., intravenous injection) of local anesthetics that can lead to systemic toxicity evident by symptoms of the central nervous system (e.g., seizures, dizziness, tinnitus, speech disorder) or the cardiovascular system (e.g., myocardial depression, arrhythmias, cardiovascular collapse) [102, 110], local delivery of anesthetic molecules can reduce these risks by decreasing the concentration of circulating drug [111]. Moreover, perineural administration of analgesics also can improve the bioavailability of the drug therefore reducing the total amount of drug needed for a desired effect. Intra-articular or perineural injection of local anesthetics are superior in that they pose a much smaller risk for respiratory arrest, toxicity, and seizures than when local anesthetics are injected into the central nervous system [102]. Therefore, delivery of local anesthetics to the perineural space surrounding hyperactive peripheral nerves may help alleviate peripheral nerve pain associated with an osteoarthritic joint while minimalizing secondary off-target effects that occur with oral analgesic treatment methods. Table 1 describes pharmacological information of common local anesthetics including combination therapies administered for peripheral nerve blocks.

Table 1.

Summary of local anesthetics used for peripheral nerve block^*.

Anesthetic	Volume (mL)	Drug (%)	Dose (mg/mL)	Type of block	Duration of analgesia (hours)	Comments	Reference
Ropivacaine	30	0.75%	7.5	subclavian perivascular brachial plexus block	11– 14	Onset and duration of sensory and motor block was similar to 0.5% (30mLs) Bupivacaine. Median time to first analgesic request was 11 hours. Quality of analgesia was “excellent” for 67% (33/49) and “unsatisfactory” for 28% (14/49) of patients.	[Vaghadia, 1999 #1770]
	32	0.50%	5.5	Subclavian perivascular brachial plexus block (C5). Additional drug (3mLs) was used to separately block the intercostobrachial and medial brachial (T2) subcutaneous nerves.	13– 14	Frequency of analgesia (92%; 22/24) assessed across brachial plexus dermatomes (C5-T1) and was not different from 0.5% bupivacaine. Side effects included hand paralysis (83%; 19/24). Study did not monitor cardiovascular toxicity.	[Hickey, 1991 #1771]
	25	0.75%	7.5	Femoral nerve block (10mL) followed by sciatic block (15mL)	7– 15	Study limited by small patient cohorts (n = 15)	[Fanelli, 1998 #1772]
	32	0.75%	7.5	axillary brachial plexus block with additional drug (4mL) used to block the intercostobrachial cutaneous nerve	8– 11	6.7% (2/30) of patients required intraoperative opioids following block. 100% (30/30) were satisfied with block. Significantly reduced mean onset time compared to 0.5% bupivacaine.	[Bertini, 1999 #1773]
	32	0.50%	5	axillary brachial plexus block with additional drug (4mL) used to block the intercostobrachial cutaneous nerve	7– 14	10% (3/30) of patients required intraoperative opioids following block. 93.4% (28/30) were satisfied with block.	[Bertini, 1999 #1773]
	45	0.50%	5	perivascular axillary brachial plexus block	11– 24	Two telephone interviews were used to assess duration of block, at 8– 11hrs and 20– 26hrs following injection. 3.3 % (1/30) patients had inadequate block and required followup general anesthesia. Average time to first postoperative analgesic was 15hrs.	[Liisanantti, 2004 #1774]
Bupivacaine	32	0.50%	5	subclavian perivascular brachial plexus block	10– 17	Median time to first analgesic request occurred was 12 hours. Quality of analgesia was “excellent” for 53% (26/49) and “unsatisfactory” for 34% (17/49) of patients.	[Vaghadia, 1999 #1770]
	25	0.50%	5	Femoral nerve block (10mL) followed by sciatic block (15mL)	9– 20	Study limited by small patient cohorts (n = 15). Adequate surgical anesthesia took up to 50 minutes.	[Fanelli, 1998 #1772]
	32	0.50%	5	subclavian perivascular brachial plexus block, intercostobrachial and medial brachial subcutaneous block	13– 14	91% (21/24) of patients reported hand paralysis. Patients had a increased incidence of Horner’s Syndrome compared to 0.5% ropivacaine. Study did not monitor cardiovascular toxicity.	[Hickey, 1991 #1771]
	32	0.50%	5	axillary brachial plexus block with additional drug (4mL) used to block the intercostobrachial cutaneous nerve	7– 14	23.3% (7/30) of patients required intraoperative opioids following block. 73.3% (22/30) were satisfied with block.	[Bertini, 1999 #1773]
	20	0.50%	5	Three-in-one block: perivascular inguinal injection to block the femoral, lateral cutaneous and obturator nerves	13– 21	Onset to analgesia (27min) was similar to patients that received 0.5% or 0.25% dose of levobupivacaine	[Urbanek, 2003 #1775]
	45	0.50%	5	perivascular axillary brachial plexus block	11– 27	Two telephone interviews were used to assess duration of block, at 8– 11hrs and 2026hrs following injection. Average time to first postoperative analgesic was 18hrs.	[Liisanantti, 2004 #1774]
Levobupivacaine	45	0.50%	5	perivascular axillary brachial plexus block	11– 27	Two telephone interviews were used to assess duration of block, at 8– 11hrs and 2026hrs following injection. 6.7 % (2/30) patients had inadequate block and required followup general anesthesia. Average time to first postoperative analgesic was 17hrs.	[Liisanantti, 2004 #1774]
	20	0.50%	5	Three-in-one block: perivascular inguinal injection to block the femoral, lateral cutaneous and obturator nerves	14– 19	Comparable to 0.5% bupivacaine with respect to duration of analgesia for three-in-one block.	[Urbanek, 2003 #1775]
	20	0.25%	2.5	Three-in-one block: perivascular inguinal injection to block the femoral, lateral cutaneous and obturator nerves	9– 14	45% of patients (9/20) reported complete sensory block after initial 60 min. following injection. Further studies needed to confirm efficacy of anesthetic effect at this dose.	[Urbanek, 2003 #1775]
Lidocaine	10	1%	__	parasacral sciatic, proximal interfacial obturator, and lateral femoral cutaneous nerve block	__	89% of patients reported successful block with a dose of 0.93% w/v (15mL)	[Taha, 2013 #1776]
Dextrose prolotherapy	30	2% Lidocaine hydrochloride (20mL) with epinephrine 1:200,000 with 5% dextrose (10mL)	__	brachial plexus block	__	Ultrasound guided injection of 2% lidocaine alone or combined with 5% dextrose produced similar sensory and motor block	[Mosaffa, 2020 #1878]
	--	0.5% ropivacaine with 5% dextrose	--	axillary brachial plexus block	12– 13	The addition of dextrose decreased the time of onset of regional block (15 min) compared to 0.5% ropivacaine alone (22 min).	[Dhir, 2008 #1879]

^*Information not provided in the publication is left blank with a dash in the box.

While local anesthetics block peripheral nerve transduction, corticosteroids may be co-administered with LA for their anti-inflammatory properties. Corticosteroids are lipophilic molecules which can cross the blood brain barrier and reduce inflammatory pain by impairing the synthesis of proinflammatory molecules that contribute to articular cartilage degradation [121–124]. Corticosteroids are either esters (e.g., triamcinolone acetate) which are water insoluble and have longer half-lives or are non-esters (e.g., dexamethasome) and are water soluble (clear non-particulate solution) and have a shorter duration of action due to rapid cellular uptake [125]. Some studies suggest that perineural administration of local anesthetic using a corticosteroid adjuvant prolongs the analgesic effect of local anesthetics however, this possible synergism or additive effect remains controversial [126, 127].

Perineural administration of local anesthetics in combination with dextrose prolotherapy has revealed possible synergism for sensory nerve block as well as promoting local regeneration and improving joint stability [128–130]. Prolotherapy is an injection treatment strategy that does not require ultrasound guidance to administer several small injections of dextrose into the surrounding ligaments, tendons, and intraarticular of adjacent joints found to be hypersensitive due to underlying OA pathology. Dextrose solution (10%−25%) administered alone causes pain due to its high osmolality and ability to induce excessive inflammation [131] but combination treatment with local anesthetics such as lidocaine (0.1%−0.5%) decreases pain following injection as well as activates regenerative processes for pain relief and functional recovery in patients [128]. In vitro studies of lidocaine combined with dextrose show that even smaller concentrations than administered clinically are capable of increasing fibroblast proliferation and increased collagen synthesis therefore contributing to matrix formation a characteristic of regeneration [131]. Therefore, formulations that combine nerve block as well as target underlying disease pathology such as inflammation or promote regeneration may provide a more effective therapeutic outcome for patients with joint degeneration as well as chronic pain.

The following section will describe the literature of local anesthetic perineural injection formulations used to manage osteoarthritic pain of the shoulder, hip, and knee joint regions.

Suprascapular nerve blocks in shoulder OA

In about half of patients that present with shoulder pathologies report their symptoms are attenuated or resolved within six months [132]. During those months patients suffering from persistent pain may seek perineural injection therapy or intraarticular injection of viscosupplements, such as hyaluronic acid, to manage symptoms of OA [76]. The suprascapular nerve provides two-thirds of the nervous supply of the shoulder joint and thus is a major target for perineural therapeutic intervention for shoulder pain [66]. Patients with osteoarthritis of the GH joint that receive perineural injections of prilocaine to the suprascapular and axillary nerves showed prolonged relief for upwards of 13 weeks as well as improved GH joint range of motion [133]. Moreover, dual administration of bupivacaine and methylprednisolone for suprascapular nerve block in treatment of shoulder arthritis also demonstrated significant pain relief during walking and at night, reduced VAS pain scores were observed at four and 12 weeks post treatment [134]. Majority of shoulder region injections target the subacromial region as opposed to the GH joint which is located deeper within the shoulder. If the rotator cuff is not injured the GH and acromion are anatomically separate allowing for both regions to be individually injected with a therapeutic agent [135, 136]. Subacromial injections can alleviate shoulder pain however, when compared to patients that received suprascapular nerve block, suprascapular nerve block was more effective at alleviating pain and improving overall shoulder function 12-weeks following treatment [137]. A caveat is that suprascapular nerve block require guided technology to be able to visualize the nerve for accurate delivery of local anesthetics.

Obturator and femoral blocks in hip OA

Patients with hip pain associated with OA are not always responsive to conventional treatment whereby, nerve block may be used to manage intractable hip pain. Articular branches of the obturator and femoral nerves that supply majority of the hip joint are likely contributors of pain symptoms. Inadequate pain relief of this joint can result in referred pain within the groin and lower extremities including the thigh and knee. In Yavuz’s study, all included participations reported “only pain” in the groin and thighs [138]. Patients that received lidocaine injection into the articular branches of the obturator and femoral nerves surrounding the hip joint reported reduced pain during walking and at night at both one- and three-months following administration [138]. In comparison, intramuscular injection of triamcinolone alleviated hip pain up to 12 weeks post-injection compared to placebo controls [139]. However, other studies revealed that corticosteroid injection for hip OA pain resulted in short term analgesia. In addition, the efficacy of intraarticular cortisone injections are debated for treatment of hip OA pain [97, 140]. In comparison, patients diagnosed with hip dysplasia as a result of OA that received dextrose prolotherapy compared to exercise therapy alone showed greater reduction in hip pain for up to 12 months [141]. Moreover, combination therapy of dextrose (12.5%) and lidocaine (0.5%) given to athletes suffering from chronic groin pain showed that on average three injections given in month intervals were sufficient to reduce pain for up to 32-months following treatment [142].

Saphenous and genicular blocks in knee OA

Pain management regiments for individuals undergoing total knee replacement commonly include peripheral neve block of the femoral or saphenous nerves, also referred to as “adductor canal” block) to manage postsurgical pain [143, 144]. More recently, perineural injection therapy of local anesthetics, corticosteroids, or dextrose prolotherapy are suggested as methods for targeting specific peripheral nerves that contribute to knee pain symptoms. When compared to exercise regiments, or saline controls, patients that received dextrose prolotherapy (intra-articular or subdermal injections) for knee OA pain reported improved WOMAC score at fifty-two weeks following treatment [145]. When compared to patients following total knee replacement that received oral or intravenous analgesic treatment of diclofenac and acetaminophen and rehabilitation, patients that received dextrose therapy surrounding the knee joint showed improvement from baseline with regards to WOMAC and VAS scoring systems up to six-months post-surgery [146]. Moreover, perineural subcutaneous administration of dextrose solution (5%) surrounding the anterior femoral cutaneous nerve of the thigh, obturator, and saphenous nerve mitigated knee pain and improved knee function [147] which interestingly was similar to patients that received low level laser therapy [148] to treat mild to moderate knee OA. Dextrose therapy was also shown to strengthen anterior cruciate ligaments which is beneficial in decreasing the risk of future injury which develop into musculoskeletal conditions such as OA and resulting in long term pain [149]. Therefore, future treatment paradigms that combine local anesthetics and dextrose solutions may be beneficial for managing knee pain while also promoting local regeneration and thereby improving joint organ integrity.

Direct knee injections of triamcinolone acetonide for osteoarthritis knee pain has shown efficacy for short term pain relief [150, 151]. However, the analgesic efficacy for long term pain using triamcinolone acetonide has shown modest improvements in pain scores 1 week following treatment and no difference at 6 weeks, as measured by visual analogue pain scores (VAS), distance walked in one minute (WD), and health assessment questionnaire (HAQ) [150]. Femoral nerve blocks are adequate analgesic approaches for knee OA however, subsequent loss of motor function can increase a patient’s risk for injury (i.e., falling). Using MRI or ultrasound guided techniques, surgeons can conduct a saphenous nerve block with considerable accuracy and reliability based on the consistency of anatomical locations of the saphenous nerve between human subjects [152]. Ultrasound or fluoroscopy guided genicular nerve block revealed comparable differences in pain relief and functional improvement for knee OA [153]. Using ultrasound guided genicular nerve block Kim and colleagues evaluated whether dual drug formulation of lidocaine alone versus lidocaine combined with corticosteroid, triamcinolone, the authors did not observe any significant differences in VAS scores between both groups at four weeks following drug administration [35].

FUTURE DIRECTIONS

Over the past few decades, the biomaterials field has spawned new therapeutic strategies for delivering drugs and promoting endogenous repair systems. Three commonly studied controlled/sustained drug delivery systems includes nanotechnologoes (e.g., liposomes) and microgels (e.g., hydrogels). For a comprehensive review of methods used for postoperative pain management refer to Brigham and colleagues [154] as well as a review on nanotechnological strategies for the treatment of osteoarthritis by Mohammadinejad and colleagues [155]. Injectable engineered systems provide controlled and/ sustained release profiles of encapsulated drug payloads, which can be used to increase therapeutic windows [156]. In addition, these biomaterial carriers offer the potential to deliver multiple drugs that can target multiple aspects of a disease environment, including inflammation and joint-related pain. Extended-release local anesthetics are raising significant attention lately due to their potential to improve analgesia and reduce adverse side effects of local anesthetics. Liposomal bupivacaine (DepoFoam bupivacaine or Exparel® (Pacira Biosciences, Inc., San Diego, CA)) is the first and currently the only FDA approved local anesthetic formulation with sustained release capabilities.

Liposomes are small vesicles in the nanometer- micrometer range that consist of phospholipid bilayer membranes. Due to the organic structure of phospholipids, drugs that are lipophilic or hydrophobic can be encapsulated between the unsaturated fatty acid tails within the bilipid membrane whereas lipophobic or hydrophilic drugs can be stored between polar heads of the phospholipids that create the core of the vesicle. Within the realm of preclinical and clinical human studies, intravenous lipid emulsions and microspheres have gained traction as possible new treatments for managing OA symptoms [156–158]. Several polymeric nanoparticles, nanofibers and hydrogel delivery systems for local anesthetics are currently under investigation [159]. Therefore, future clinical use of controlled drug delivery systems for OA treatment may provide a strategy that can promote sustained pain relief while a patient attends rehabilitation thereby, improving joint functionality. Liposomal encapsulation of bupivacaine hydrochloride has been shown to reduce systemic drug levels, decrease systemic toxicity, and prolong analgesia [160–162]. Forthcoming strategies using nanotechnologies may be used to deliver cell-based therapies, genes, or biologically active substances (e.g., growth factors) for the development of novel formulations that manage OA symptoms [155].

Advances in guided technology in Ultrasonography has improved the diagnostic, medicinal and physiotherapeutic treatment of musculoskeletal conditions [163]. Ultrasonography or ultrasound (US) is ideal for treating musculoskeletal conditions because it allows for the identification of anatomical locations for more accurate drug injections and decreases risk of accidental intravascular injection which can lead to CNS and cardiotoxicity [164]. A patient’s risk of developing systemic toxicity is 1:1600 with the use of ultrasound-guided regional anesthesia as compared to a 1:1000 risk when nerve stimulators are used to locate peripheral nerves [110]. The use of ultrasound allows for the administration of smaller volumes of drug thereby reducing the amount of drug that may be taken up intravascularly. The transducer at the end of the device that contacts the body emits acoustics waves across the skin and when those pulses encounter muscle, blood vessels, or bone. The resultant pulses that reach the transmitter are translated into a physical image of internal bodily structures. Many studies have shown that US-guided technology compared to other radiographic imaging techniques is a superior method for identifying nerves for delivery of local anesthetics [165]. Although the use of US requires specific equipment and training, the development of portable devices with smart-phone sync capabilities have increased the ease of use of US in clinical settings. As technology continues to improve and decrease the cost of machines, US may hopefully become more readily available for preclinical and clinical use. Image guided perineural injections overcomes a significant challenge with local therapeutic injections in that it allows you visualize nerve of interest to target for diagnostic or therapeutic purposes. Therefore, improving the accuracy of injections with less risk of vascular damage and nerve injury thereby increasing the number of nerves that may be accessed and targeted for joint-related pain relief.

CONCLUSION

In summary, clinical pain assessment that helps determine peripheral contributions of joint-related pain may improve pain management strategies. Local anesthetic injections can be used to inhibit hypersensitivity of peripheral nerves that supply and may contribute to joint-related pain symptoms. By using advanced imaging techniques such as US, local anesthetic may be delivered with higher accuracy which can increase analgesic efficacy (Figure 9). Local anesthetics have the potential to provide long-lasting analgesia when combined with biomaterial drug delivery systems, as well as novel combination formulations that extend the duration of analgesia with minimal side-effects may provide a more effective approach for managing osteoarthritic pain.

Fig. 9. Summary schematic illustrating the use of guided imaging for delivery of analgesics for the treatment of OA pain.

Clinically administered local anesthetics are described in addition to clinically used intra-articular therapies and emerging biomaterial drug delivery systems that may be used to improve the treatment of OA pain.

Fig. 2. Radiographic X-Ray images of mild knee osteoarthritis.

(a) Posterior-Anterior standing, (b) Rosenberg standing, and (c) lateral standing views of the right knee were performed. There is some mild narrowing of the medial joint space. The lateral joint space and patellofemoral joint spaces are normally maintained. There is some minimal spurring involving the lateral corner of the patella. There is no joint effusion. Otherwise, no significant bony, joint space or soft tissue abnormalities can be seen. Arrows denote physical changes within the joint.

List of abbreviations

(OA)

Osteoarthritis

(JSN)

Joint space narrowing

[MRI]

Magnetic resonance imaging

(OCT)

Optical coherence tomography

(US)

Ultrasound

(AP)

Anterior-Posterior

(VRS)

Verbal Rating Scales

(VAS)

Visual Analog Score

(NRS)

Numeric Rating Score

(WOMAC)

Western Ontario and McMaster Universities Osteoarthritis Index

(AAOS)

American Academy of Orthopedic Surgeons

(SC)

Sternoclavicular

(AC)

Acromioclavicular

(GH)

Glenohumeral joints