1. OVERVIEW AND DESCRIPTION
Injectable agents are often used diagnostically and/or therapeutically to address a diverse set of musculoskeletal and neuropathic complaints (Table 1)1. These agents are administered percutaneously into neuromusculoskeletal structures or intrathecally. There are a variety of agents used in current practice. The goal of this article is to summarize the mechanism of action, indications, contra-indications, adverse effects, and current practice guidelines for the most frequently encountered injectable pharmacologic treatments.
Common indications for an injectable agent include musculoskeletal pathology, myofascial trigger points, peripheral nerve blocks, spasticity, chronic pain, and neuropathic pain. Musculoskeletal pathology include osteoarthritis, baker cysts, bursitis, rotator cuff arthropathy and adhesive capsulitis.2 Trigger point injections address regional pain syndromes, including myofascial pain, low back/neck pain, and headache.3 Peripheral nerve blocks are often performed on the suprascapular, lateral femoral cutaneous, and femoral nerves, and they are performed for spasticity and neuropathic pain.4 Intrathecal systems are used for long-term symptomatic management of malignancy-related chronic pain6 or in spastic hypertonia caused by cerebral palsy, spinal cord injury, or brain injuries.4
Table 1. Locations Commonly Used for Injectable Agents
The agents most commonly used include local anesthetics, corticosteroids, hyaluronic acid, opioids, baclofen, clonidine and ziconotide.
- Local anesthetics are membrane-stabilizing drugs, acting mainly by inhibiting voltage-gated sodium channels in the neuronal cell membrane.2,4 Local anesthetics are frequently used in combination with corticosteroids.
- Corticosteroids mediate anti-inflammatory properties through glucocorticoid effects, changing white blood cell traffic, altering cytokine levels, and inhibiting phospholipase A2 function. They have antinociceptive effects by a direct stabilization on neural membranes and inhibition of C-fiber transmission.1
- Hyaluronic Acid is a naturally occurring molecule located in the synovial fluid that provides the visco-elastic properties to the synovial fluid. Intra-articular injection of hyaluronic acid is thought to provide proteoglycan and glycosaminoglycan synthesis, anti-inflammatory, mechanical, subchondral, and analgesic effects15.
- Opioids, administered neuraxially, act at substantia gelatinosa receptors through inhibition of presynaptic neurotransmitter release and postsynaptic neuronal hyperpolarization.6
- Baclofen is a GABA-B agonist, decreases excitatory amino acid release, and inhibits the release of substance P.6
- Clonidine is an alpha-2 agonist that is primarily used in essential hypertension to lower blood pressure. It acts centrally to inhibit sympathetic vasomotor centers. It has also been found that alpha-2 agonists act presynaptically in the spinal cord and bind to alpha-2 receptors on small primary afferent neurons, resulting in hyperpolarization and diminished release of neurotransmitters involved in relaying pain signals.2
- Ziconotide is the synthetic equivalent of snail venom, which blocks primary nociceptive afferents neurotransmission6.
- Platelet rich plasma is autologous whole blood that is centrifuged to extract a platelet-concentrated layer. The platelet rich plasma, when reinjected back into the patient (joint, tendon, ligament, etc.), become activated and in turn release growth factors, such insulin-like growth factor 1, vascular endothelial growth factor, platelet-derived growth factor, among several others21,22.
Administration of these agents has historically been performed percutaneously using landmark guidance. In-office ultrasonography has become increasingly available in many settings, and its use for joint and soft tissue injections has increased. Many of the studies on corticosteroid injections using ultrasound guidance have shown superior accuracy to that of landmark-guided injections20. Evidence also shows that less experienced providers can be more accurate with ultrasound guidance20. Ultrasound guidance of these agents should be considered for targets near large vascular structures, deeper anatomic structures, and for patients in whom non-guided injections have failed.1,5
2. RELEVANCE TO CLINICAL PRACTICE
The most common medications used for injection therapy to treat musculoskeletal pain are corticosteroids and local anesthetics.7 There are various corticosteroids available and can be categorized by particularity, solubility, and duration. Particulate (hydrophobic) steroids such as methylprednisolone, betamethasone, and triamcinolone must undergo hydrolysis, which lowers their solubility and elongates the duration of action. For example, Triamcinolone hexacetonide is the least soluble, and therefore the longest lasting. Betamethasone is the most soluble in the group and has the shortest duration.8 Other corticosteroids range in solubility (Table 2).
Some trials have also favored triamcinolone to be superior at pain reduction in the initial weeks after injection when compared to methylprednisolone and betamethasone.23 Few studies have investigated the efficacy or duration of action of the various corticosteroids for specific injections. However, a systematic review found that the results of corticosteroid compared to placebo revealed reduction in pain 1-week post injection, but not beyond. 23 Of note, this review was limited due to study selection criteria. In addition, a 2009 Cochrane review of IA corticosteroids for the treatment of knee osteoarthritis concluded that corticosteroids were more effective than placebo in reducing pain at 1–2 weeks’ post-injection but not after. Thus, guidelines cannot recommend for or against corticosteroid use. However, based on prior studies, the indication should be for short term pain relief. 28
The standard approximate doses for intraarticular injections are outlined in Table 3. Triamcinolone preparations are the most frequently used corticosteroid and are approved by the US FDA and in Europe. 26
Table 2. Steroid Solubility
|Steroid||Solubility (% weight/volume)|
Table 2 is adapted from Lavelle W, Lavelle ED, Lavelle L. Intra-articular injections. Med Clin North Am. 2007; 91:241-250.
Table 3. Corticosteroid Suspensions for Intra-articular Injection*
|Preparations||Concentration (mg/ml)||Usual Dose (mg)|
|Bethamethasone acetate and sodium phosphate||6||1.5-6|
*Note the amount injected varies depending on the joint size
Table 3 is adapted from D Neustadt. Intraarticular injections for osteoarthritis of the knee. Cleveland Clinic Journal of Medicine. 2006; 73; 897-911.
Contraindications for corticosteroid injection are as follows:7
- Skin infection overlying injection site
- Broken skin at injection site
- Septic arthritis/bursitis
- Febrile illness
- Systemic bacteremia
- Known hypersensitivity to corticosteroid agent
- Unstable Joint
- Prosthetic joint
- Osteochondral/intraarticular fracture
- Severe joint destruction
- Unstable coagulopathy
Adverse effects of corticosteroid injections are infrequently encountered. The most common and potentially serious complication from injection is infection. Strict adherence to universal precautions is recommended. Other local adverse effects include the following: 8,9
- Post-procedure pain
- Subcutaneous atrophy at injection site
- Skin depigmentation
- Tendon and ligament rupture
- Calcification of soft tissue structures
Systemic effects are rare and include Cushing syndrome and elevated blood glucose in diabetic patients.8,9 Alteration of menses as a result of estradiol suppression can occur due to corticosteroids effect on the hypothalamic-pituitary axis.29
The two most commonly used local anesthetics are lidocaine and bupivacaine. Lidocaine is a short-acting amino amide local anesthetic with rapid onset and short duration. The maximum dosage is 4.5 mg/kg up to 300 mg. Onset is 2-5 minutes and lasts between 2-3 hours. For safe IA injections, it is recommended to administer no more than 100 mg in 5 ml or 10 ml aliquots.25, 27,, 29 Bupivacaine, also an amide, has a longer onset and duration. Compared to corticosteroids, local anesthetics have a higher potential for adverse systemic effects; the risk rapidly escalates with higher dosages. The maximum dose for bupivacaine is 2mg/kg up to 175mg. Peak onset is 30-45 minutes and has a variable duration of 5-15 hours.31 Physicians should strictly calculate maximum doses based on the patient’s total body weight.31
Local anesthetic toxicity can present with symptoms of central nervous system excitation, including, but not limited to the following: 8,9
- Tingling around the mouth
- Blurred vision
Once toxicity has progressed, seizures followed by loss of consciousness and respiratory depression can develop. Cardiovascular effects include hypotension, bradycardia, arrhythmias, and cardiac arrest. Bupivacaine has the potential to cause toxicity at much lower dosages than lidocaine because of its increased solubility. Furthermore, bupivacaine is more cardiotoxic due to its increased affinity for cardiac sodium ion channels. Of note, new studies have shown that various local anesthetics such as lidocaine and bupivacaine have chondrotoxic effects that are worsened by co-administration of corticosteroids.30
In addition to duration of action, clinicians should factor in the potential for chondrotoxicity when debating choice of local anesthetic. Lidocaine, bupivacaine, mepivacaine, and higher doses of ropivacaine have all been shown to have chondrotoxic effects. Ropivacaine seems to be the least harmful of the commonly used local anesthetics when used at a dose of 0.5% or less.25
Viscosupplementation/Hyaluronic Acid (HA)
HA is a natural occurring glycosaminoglycan molecule and part of normal synovial fluid and cartilage extracellular matrix. In osteoarthritis, there is age related decreased cellularity and glycosaminoglycan content which contributes to cartilage matrix degeneration. HA functions in the joint by enhancing the viscosity and the elastic nature of synovial fluid which acts as a shock absorber. Therefore, by injecting HA, it may restore normal viscoelastic properties of the synovial fluid and improve its shock absorbing effects. Viscosupplementation is also thought to have anti-inflammatory effect on the synovial articular cartilage, therefore improving the homeostasis of the joint. 27,32
HA is produced from harvested rooster combs or through in vitro bacterial fermentation. There are numerous injectable forms of HA that are now FDA approved. Each differs by molecular weight, half-life, concentration, molecular structure, frequency, cost, and injection volume. Some examples are sodium hyaluronate, Hylan G-F 20, and high molecular weight hyaluronan. The higher molecular weight formula shows greater evidence for disease modifying effects for mild knee osteoarthritis. However, variability within the literature demonstrates equivocal evidence. A recent meta-analysis by Cochrane Database Review showed a series of 3 to 5 injections was efficacious by 4 weeks, with maximum effectiveness at 8 weeks, lasting up to 24 weeks when compared to placebo. 22
This is generally safe for use in patients with knee osteoarthritis, with the only adverse effect being local reaction in the injected joint. However, recommendations supporting the use of HA in knee osteoarthritis are mixed and vary in practice. 27,32
Though HA has been studied most in the setting of knee osteoarthritis, there are some studies showing potential benefit in osteoarthritis of other joints. Namely, HA has been shown to be safe and effective in ankle osteoarthritis, though its benefit compared to corticosteroid injection has not been well-studied.45,47 Similarly, HA has been shown to be effective in shoulder arthritis, though with unclear benefit compared to corticosteroid injection.45,46,48 Studies for HA in hip arthritis have been less promising, where existing studies show no superiority when compared to placebo.45
Intrathecal baclofen is often used to manage refractory lower extremity spasticity.6 Baclofen is a centrally acting muscle relaxant that is thought to act at GABA receptors. Baclofen’s adverse effects include flaccidity, weakness, constipation, urinary retention, sedation, and hypotension. Baclofen overdose can lead to respiratory depression, seizures, and death.6Abrupt cessation of baclofen is similarly dangerous, and withdrawal can occur when patients are noncompliant with scheduled pump refills or from mechanical issues with the pump or catheter. Replacement with oral baclofen may not be adequate to control withdrawal symptoms.6 Symptoms of Baclofen withdrawal include the following:
- Labile blood pressure
- Muscle rigidity
Strong evidence supports the use of intrathecal infusions for cancer-related pain and neuropathic pain.6,10 Less convincing data favor the use of long-term intrathecal analgesic therapy for noncancer-related pain.6,10
Intrathecal therapy is most often employed to manage refractory chronic pain symptoms.6 Intrathecal analgesics do not alter pathologic processes that cause pain. Rather, they enhance patient analgesia, promote functional gains, and minimize adverse effects of treatment alternatives, such as oral or parenteral analgesics.6
Opioids induce analgesia by causing hyperpolarization of nerve cells, inhibition of nerve firing, and presynaptic inhibition of neurotransmitter release. Morphine acts through mu receptors in lamina I and II of the substantia gelatinosa of the spinal cord, and decreases the release of substance P, which modulates pain perception in the spinal cord. Morphine may also inhibit the release of excitatory neurotransmitters from nerve terminals carrying nociceptive stimuli.6
Morphine is the criterion standard for intrathecally administered analgesics and is the only opioid Food and Drug Administration (FDA) approved for intrathecal use.6 Other opioids, such as hydromorphone, fentanyl, sufentanil, methadone, and buprenorphine, and another controlled substance, midazolam, have been used in clinical trials.10 Primary complications of intrathecal opioid therapy include respiratory depression, edema, opioid-induced hyperalgesia, and suppression of the hypothalamic-pituitary axis. Long-term intrathecal opioid can lead to catheter-tip granuloma formation.6,10 This may be related to opioid infusion concentration. These can be large enough to cause neurologic dysfunction and cord compression.6,10
Various agents are often used in combination with opioids to achieve optimal analgesia. Local anesthetic agents, such as bupivacaine, can be added to the mixture, with uncontrolled and nonrandomized studies supporting this practice.10 Local anesthetics block nerve conduction of sensory impulses from the periphery to the central nervous system. They inhibit sodium channels in the nerve membrane. The small, unmyelinated nerve fibers that relay pain impulses are sensitive to the effects of local anesthetics. Combinations of morphine or hydromorphone with bupivacaine have been shown to be stable for intrathecal use at 90 days.10
Clonidine is an alpha-2 agonist that is primarily used in essential hypertension to lower blood pressure. It acts centrally to inhibit sympathetic vasomotor centers. It has also been found that alpha-2 agonists act presynaptically in the spinal cord and bind to alpha-2 receptors on small primary afferent neurons, resulting in hyperpolarization and diminished release of neurotransmitters involved in relaying pain signals.6 Clonidine is the only alpha-2 agonist FDA approved for intrathecal use.6 Caution must be exercised in individuals who have hypotension. Abrupt discontinuation of intrathecal clonidine can result in rebound hypertension.6 Side effects of clonidine include the following:
- Dry mouth
Ziconotide is FDA approved for intrathecal use.6 It is the synthetic equivalent of snail venom, which blocks primary nociceptive afferents neurotransmission. Side effects include nausea, mental status changes, and visual and vestibular difficulties.6
3. CUTTING EDGE/UNIQUE CONCEPTS/EMERGING ISSUES
The latest trend in nonoperative musculoskeletal care is the use of autologous agents, such as platelet-rich plasma (PRP). PRP is harvested directly from the patient by withdrawing a small quantity of whole blood and then spinning it down in a centrifuge to extract out a platelet-concentrated layer. The platelets, when reinjected back into the patient (joint, tendon, ligament, etc), become activated and undergo degranulation, releasing transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), insulin-like growth factor, vascular endothelial growth factors, epidermal growth factors and basic fibroblast growth factor 2. These growth factors serve as chemical mediators to orchestrate the body’s own natural healing response and results in the formation of stronger, more organized, normative appearing tissue. The new healthier tissue takes the place of the old abnormal tissue.
More recently, results of a large randomized clinical trial revealed that 84% of patients with chronic tennis elbow who had failed other nonoperative treatments were successfully treated using PRP.12,13A recent 2019 meta-analysis showed significant improvement in WOMAC pain scores for people with knee osteoarthritis after injections of PRP compared to Hyaluronic Acid (HA). At 6 months, WOMAC scores showed more relief with PRP injections than those in the HA group (Mean difference = 1.24, 95% CI =–1.94 to -0.53, P= 0.0006) and again at 12 months (Mean Difference = -1.75, 95% CI = -2.50 to -1.01, P < 0.000001).33
PRP’s main drawback is there is no standard method for production or quality measures. There exist four main categories of PRP, 2 liquid solutions and 2 gel solutions. These include pure platelet rich plasma which is absent of leukocytes (P-PRP), Leukocyte and platelet rich plasma (L-PRP), pure platelet-rich fibrin (P-PRF) and leukocyte and platelet rich fibrin (L-PRF).37 The two fibrin solutions exist in a gel only formation only and cannot be used for injection. Within these categories there is a lack of standardization.37 Platelet and leukocyte concentration, use of anticoagulants, and centrifuge speed/time can vary widely between studies. This may cause significant differences in the amount of growth factors released.35
Autologous conditioned serum (ACS) is another biologic agent that may have benefit via intraarticular injection to help alleviate joint pain resulting from osteoarthritis. Autologous conditioned serum is derived by incubating a patient’s venous blood in a specialized syringe with glass beads to induce the release of anti-inflammatory cytokines, such as interleukin (IL)-1 receptor antagonist, IL-4, IL-10, and IL-13, and TGF-β. ACS serum is then aliquoted for reinjections and can be frozen for future use. A randomized, double blinded, placebo-controlled study found ACS injections into the knee to show greater improvement in WOMAC pain scales when compared to hyaluronic acid and saline. Baseline WOMAC pain was measured compared to follow up visits. Reduction of pain as measured by WOMAC criteria showed, at 7 weeks ACS: -2.47 vs HA:-1.26 vs Saline: -1.37; at week 13 ACS: -2.85 vs HA: -1.16 vs Saline: -1.25; at week 26 ACS: -2.76, vs HA: -1.30 vs Saline: -1.18.36 The pain reduction between ACS compared to HA and saline were statistically significant with P value P < 0.001 for each comparison36
More recently, there have been a number of trials studying extended-release (ER) triamcinolone acetonide. In this formulation, the active agent is incased in microspheres that release triamcinolone over time, which in theory prolongs its presence in the synovium and decrease acute systemic side effects, such as hyperglycemia. Several phase III trials show favorable results in pain and function scores compared to the traditional crystalline suspension when used for knee osteoarthritis.24 One such trial compared the extended-release formulation again saline as well as traditional triamcinolone in crystalloid. When compared against saline, triamcinolone acetonide ER recipients showed a statistically significant improvement of > 30% (67.3 vs. 53.0% at week 12; p < 0.05 at weeks 1–13) and > 50% (52.3 vs. 37.1% at week 12; p < 0.05 at weeks 1–16 and 18). 38 When compared against triamcinolone in crystalloid, there was an improvement in pain scores, but it was not a statically significant difference. Triamcinolone ER was also measured form weeks 12-24 against saline and continued to show improvement of pain scores.38 Unfortunately triamcinolone in crystalloid was not measured for the extended timeframe in this study. These “extended-release” formulations may become more prevalent for large joint injections in the future.
Botulinum toxin has been recently studied for its use in joint pain. Botulinum toxin A is a neurotoxin produced by Clostridium botulinum17. The U.S. Food and Drug Administration approved BoNT/A for its muscle paralyzing effects in neuromuscular disorders, such as spasticity, cervical dystonia and blepharospasm17. However, recent animal model studies have shown a potential antinociceptive effect in painful joint conditions 16,18,19. One study showed similar efficacy to intraarticular steroids.14
Prolotherapy is a procedure in which a substance, commonly hypertonic dextrose, that promotes growth of normal tissue is injected into a joint or tendon. In one study patients were evaluated 12 weeks after the injection of hypertonic dextrose or hyaluronic acid and compared using the Knee Injury and Osteoarthritis Outcome Score (KOOS). No significant differences were found between the two groups in regard to KOOS scores (P<0.001).44 Although this study found prolotherapy to be equal to hyaluronic acid it is important to note recommendations supporting the use of HA in knee osteoarthritis are mixed and vary in practice. 27,32
4. GAPS IN KNOWLEDGE/EVIDENCE BASE
According to Cochrane Reviews, there is currently insufficient data from randomized controlled trials, and a need for further research, regarding the efficacy of corticosteroid injectables for shoulder pain, rotator cuff disease, adhesive capsulitis, Achilles tendinopathy, and de quervains tenosynovitis.39,40,41 Further research is needed on whether intraarticular injections with image guidance improves osteoarthritis treatment efficacy.5 However, a 2012 Cochrane Review found that there was no improvement in pain, function or range of motion when comparing ultrasound guidance to anatomic glucocorticoid injection for subacromial injections in the management of shoulder disorders.42 Limited studies are available on cost-effectiveness and cost-utility analysis of intraarticular and intrathecal injections.4 Future studies are needed on the role of intrathecal analgesia, especially to which pain conditions or subpopulations are most responsive, or which agent combinations are most appropriate.6 Moderate and high-quality evidence of outcomes for nonoperative treatment for spinal stenosis with radicular symptoms, specifically with regards to the most efficacious injectate, are lacking.43
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- Mishra A, et al. Platelet rich plasma significantly improves clinical outcomes in patients with chronic tennis elbow. Abstract presentation at: Annual Meeting of the American Academy of Orthopaedic Surgeons; March 19-23 2013; Chicago, IL.
- Mishra A, et al. Platelet rich plasma significantly improves clinical outcomes in patients with chronic tennis elbow. Am J Sports Med. In Press.
- Boon AJ, Smith J, Dahm DL, et al. Efficacy of intra-articular botulinum toxin type A in painful knee osteoarthritis: a pilot study. PM R. 2010;2:268-276.
- Altman, R., Manjoo, A., Fierlinger, A., Niazi, F., & Nicholls, M. (2015). The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review. BMC Musculoskeletal Disorders, 16(1).doi:10.1186/s12891-015-0775-z
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Original Version of the Topic
Armando S. Miciano, MD, Jonas Sokolof, DO, Devi Nampiaparampil, MD. Injectable agents. 09/20/2013.
McCasey Smith, MD, MS
Nothing to Disclose
David Sherwood, DO
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Lauren Neuman, DO
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Stephen Bai, MD
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Anthony Jackson, MD
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Derek Shirmer, DO candidate
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