Injection Therapy for Common Chronic Pain Conditions of the Foot
Karina Charipova
Kyle Gress
Ivan Urits
Omar Viswanath
Hisham Kassem
Alaa Abd-Elsayed
INTRODUCTION
Interventions to alleviate chronic foot pain range from conservative measures such as rest to semi-conservative approaches like injections, all of which aim to avoid invasive surgery. Historically, costly surgical interventions with questionable efficacy have been deployed at a cost to Medicare of almost a billion dollars a year.1 Here, the authors will present semiconservative measures as an alternative to invasive procedures.
INJECTABLE SUBSTRATES
There are a variety of injectable substrates that, through different mechanisms, have the potential to provide relief to chronic foot pain.
Corticosteroids
Corticosteroids are the mainstay of treatment, the old guard. They have been used extensively for nonsurgical treatment of inflammatory and degenerative conditions.2 Through a complex mechanism that acts directly on the nuclear steroid receptor, these injections interrupt the inflammatory and immune cascade to help decrease swelling, redness, and tenderness at the site of action.3
Hyaluronic Acid
Hyaluronic acid is a naturally synthesized glycosaminoglycan that occurs in the synovial fluid of joints after being created by fibroblasts, chondrocytes, and synovial cells. In diseased, inflamed, and osteoarthritic joints, hyaluronic acid is diluted through the invasion of inflammatory cytokines, free radicals, and proteolytic enzymes.4 The dilution process prevents hyaluronic acid from acting as a shock absorber and lubricant.4 Augmentation of affected joints with additional injected hyaluronic acid resets the balance within the synovial fluid and provides the elasticity needed to protect the surrounding bone.3
Alcohol
Alcohol injections are usually mixed with local anesthetic and have been used for approximately the past 20 years.5 The goal of this treatment is to stimulate chemical neurolysis to prevent the transmission of painful stimuli from the periphery to the central nervous system.6 This technique is usually reserved for neuromas that are refractory to other treatments.
Platelet-Rich Plasma
Platelet-rich plasma (PRP) supercondenses degranulated platelet growth factors along with naturally occurring thrombin and cytokines to help speed up the naturally occurring growth process.7 This happens specifically via the improvement of chondrogenesis, cell proliferation, angiogenesis, cell differentiation, and bone remodeling, among other processes.8 It is hypothesized that over 300 distinct proteins could be involved in these injections.9 It should
be noted that PRP injections are significantly more expensive than both corticosteroid and hyaluronic acid injections.
be noted that PRP injections are significantly more expensive than both corticosteroid and hyaluronic acid injections.
Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) are naturally appearing cells that have a slew of capabilities including anti-inflammatory properties, immune regulation, and immune suppression.3 There are a number of proposed mechanisms that explain how these cells function, but at this time consensus is lacking.9 MSC, albeit used for the treatment of chronic foot pain, is poorly understood and is far more expensive than most other available treatments.
Capsaicin
Capsaicin, a natural chemical found in hot peppers, serves as an agonist to the vanilloid receptor. This receptor naturally responds to noxious stimuli that are associated with the burning sensation that results from consumption of spicy foods.10 While a side effect of the injection is a local burning sensation, it does have the capacity to provide a transient, reversible loss of nociceptor afferents that help with a temporary reduction of pain.11
Amniotic/Placental (Clarix Flo) Injections
Amniotic membrane/umbilical cord-based particulate injections have recently been researched to determine potential efficacy in a variety of conditions. Like other biologic products, amniotic membrane/umbilical cord-based injectables aim to accelerate healing and regeneration using allogenic growth factors.12 Clarix Flo is the only one currently available on the market. It has been studied as an intervention for multiple different disease processes in the lower extremities. In a randomized trial in patients with plantar fasciitis, cryopreserved amniotic membrane injections are compared similarly in efficacy to corticosteroid injections with a better safety profile.13 In limited data, these injections showed to have beneficial effects in patients with chronic diabetic foot ulcers.14 Another recent study showed that, when compared to saline treatment, treatment with amniotic membrane/umbilical cord injections correlated with a slowing of the osteoarthritis disease process.15 A 2020 study looked at injections as a treatment for lower extremity neuropathy, with findings showing positive response including reduction of pain and no complications.16 While still needing more research, amniotic membrane/umbilical cord injections provide a potentially promising future of safer, more effective injectables useable for a whole host of ailments.
INDICATIONS
Morton Neuroma
Morton neuroma characterizes a burning pain in the forefoot, most commonly in the third intermetatarsal region.17 This metatarsalgia results from inappropriate activation of the interdigital nerve secondary to damage resulting from the nerve bulging distally to the metatarsal transverse ligament.17 The pain usually presents in an older, active female with a history of dancing or running.18 The discomfort is frequently exacerbated by wearing tight-fitting shoes.18 In some cases, the pain can be diffuse and present as numbness of the entire foot.17 It can also be described, especially when wearing shoes, as feeling as though one is stepping on a marble or a rock stuck in their shoe.17 In order to make a diagnosis, the physician performs the Mulder maneuver, wherein metatarsal pressure causes a distinct click.18 The diagnosis can be supported by the Silversklöld test, which denotes an exceptionally tight gastrocnemius muscle.18,19 In these patients, an examination of their shoes reveals an abnormal wearing pattern along the distal portion of the heel.18,19 Historically, a surgical neurectomy was performed to treat Morton neuroma.19 However, given recent exploration of potential nonoperative interventions, injections of corticosteroids, hyaluronic acid, capsaicin, and alcohol have started to gain favor.19 Multiple studies have shown that corticosteroid injections with a local anesthetic component have statistically significant short-term analgesic effects that last weeks to months.20 Side effects of these injections include pain at the injection site, tissue atrophy, “steroid flare,” and pigment
alterations.21 Hyaluronic acid has been shown, through retrospective research, to significantly decrease subjective pain through a series of injections that induce analgesia lasting over 1 year.22 While there have been hypotheses that these injections facilitate the regeneration of damaged axons, the research at this time is incomplete.23 Hyaluronic acid should be thought of simply as symptom management that acts by decreasing inflammation.23 Small sample double-blinded studies have shown that capsaicin injections have the potential to provide a significant reduction in pain that lasts approximately 1 month.10 The patients in these studies were injected with combined capsaicin and local anesthetic solution. While this has not been studied enough to provide a formal recommendation, the data are promising in suggesting that capsaicin can be used in patients with pain refractory to more conventional injection treatments. Alcohol injections have been studied even more recently, with much less historical data to support a basis for trial design. The most meaningful finding has been a trend showing that increasing the concentration of alcohol increases the analgesic response, which is unfortunately short-lived and statistically insignificant.24 Alcoholic injections require more research before evidence-based recommendations can be created; right now, they should be used only for the most refractory cases.
alterations.21 Hyaluronic acid has been shown, through retrospective research, to significantly decrease subjective pain through a series of injections that induce analgesia lasting over 1 year.22 While there have been hypotheses that these injections facilitate the regeneration of damaged axons, the research at this time is incomplete.23 Hyaluronic acid should be thought of simply as symptom management that acts by decreasing inflammation.23 Small sample double-blinded studies have shown that capsaicin injections have the potential to provide a significant reduction in pain that lasts approximately 1 month.10 The patients in these studies were injected with combined capsaicin and local anesthetic solution. While this has not been studied enough to provide a formal recommendation, the data are promising in suggesting that capsaicin can be used in patients with pain refractory to more conventional injection treatments. Alcohol injections have been studied even more recently, with much less historical data to support a basis for trial design. The most meaningful finding has been a trend showing that increasing the concentration of alcohol increases the analgesic response, which is unfortunately short-lived and statistically insignificant.24 Alcoholic injections require more research before evidence-based recommendations can be created; right now, they should be used only for the most refractory cases.
Achilles Tendinopathy
Achilles tendinopathy results from repetitive stress causing inflammation of the tendon created by the aponeurosis of the gastrocnemius and soleus muscles that insert into the calcaneus.20 Risk factors include height, weight, lack of ankle stability, age, sex, and vascularization of the tendon.25 The diagnosis is usually clinical with patients complaining of tenderness at the posterior heel, especially when wearing shoes.26 The physical examination is notable for tenderness to palpation and swelling at the insertion point and can be confirmed with ultrasound showing inflammation and degeneration.26 Historically, magnetic resonance imaging (MRI) was used to diagnose Achilles tendinopathy; however, recent studies comparing MRI to ultrasound show that ultrasound diagnosis is more accurate, is less costly, and allows the dynamic assessment of movement, making it first line for diagnostics.23,24,27,28
The first-line treatment for Achilles tendinopathy is lifestyle changes that include rest, analgesics, and ice to help prevent inflammation.29 Unfortunately, the Achilles can be irreversibly damaged.29 Surgical interventions are also an option but usually rely on the removal of pathologic tendon segments.29 This process inflicts trauma to promote healing and has been reported to have results that range from mixed to unsatisfactory.29 Injection techniques have recently shown promise but still lack the research necessary to make formal recommendations. The most promising data have come from multiple PRP studies that have demonstrated a decrease in overall pain score.29,30 Unfortunately, conflicting data have also shown that PRP is no better than a placebo.31
Tarsal Tunnel Syndrome
Tarsal tunnel syndrome is a compressive neuropathy of the posterior tibial nerve or one of its distal branches. This pain originates from a narrowing of the tarsal tunnel, a space bordered by the flexor retinaculum, medial malleolus, talus, calcaneus, and tibia.32,33 Symptoms include paresthesia and difficulty walking that can lead to atrophy.34 The narrowing can have multiple etiologies but is most commonly caused by soft-tissue hypertrophy, an inflammatory process, lower leg edema, trauma, or a space-occupying lesion.35 Diagnosis should be signaled by a positive Tinel sign at the tarsal tunnel, and it can be confirmed with either nerve conduction studies or an MRI.33,36
As with carpal tunnel syndrome, the mainstay of treatment has historically been lifestyle changes followed by surgical interventions.37 Unlike carpal tunnel, tarsal tunnel syndrome has a much lower incidence, and randomized controlled studies have not yet evaluated the efficacy of injectable substrates in its treatment. Based on similarities to other neuropathies, the use of corticosteroids and anesthetics is usually attempted before surgical intervention so long as there is no distal neurologic deficit.35 A small study showed that of 9 patients who received corticosteroid injections, 6 of them experienced symptomatic relief. Still, only 2
patients demonstrated objective nerve conduction improvement as compared to preinjection baselines.38 While not an evidence-based practice, using corticosteroid injections as either an alternative or precursor to surgical interventions seems reasonable, albeit necessitating further study.
patients demonstrated objective nerve conduction improvement as compared to preinjection baselines.38 While not an evidence-based practice, using corticosteroid injections as either an alternative or precursor to surgical interventions seems reasonable, albeit necessitating further study.
Plantar Fasciitis
Plantar fasciitis is the painful result of mechanical overloading causing tissue degeneration along the dorsal foot, specifically the heel.39 This biomechanical overuse injury can usually be seen in individuals who repeatedly load their foot, such as athletes and runners, especially in the elderly population; the overall prevalence is as high as 10%.40 Further risk factors include obesity and jobs that include long periods of standing. A diagnosis is made clinically, which includes point tenderness at the medial tubercle on the calcaneus that is worsened by loading and is also worse earlier in the day.39
Treatment of plantar fasciitis, like that of the other inflammatory conditions above, usually begins with conservative measures such as orthotics to offload the heel.41 If unsuccessful, steroids have been found to be helpful in the short term, acting for at most 1 month after injection.41 PRP was compared to steroids and was found to be similar in efficacy, with no difference between the groups at 1-, 3-, 6-, or 12-month intervals, which, when combined with previous studies, makes it unclear if injections are at all beneficial.39,42 In lieu of these conflicting results, a trial was performed comparing steroid injections, PRP, and shock wave therapy, an ultrasound-based noninvasive treatment.43,44 This study found that corticosteroid injection was more effective from time point zero to the time point 3 months later. At the same time, PRP was more effective from month 3 to month 12.44 Shock wave therapy provided mixed results but might be effective for the first 6 months.44 It should be noted that none of the treatment modalities showed even marginal benefit after the first 12 months, which suggests that long-term treatment is difficult.44 While again no definitive recommendation can be made, corticosteroids and PRP have a mildly decreased requirement for reinjection or surgery, and the decision to inject should be weighed against the cost of injection and proceed on a case-by-case basis.45

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