Injectable Agents

Overview and Description

Injectable agents are widely utilized in the management of musculoskeletal and neurologic conditions, including osteoarthritis, bursitis, adhesive capsulitis, myofascial pain, spasticity, neuropathic pain, and cancer pain. Administration routes are tailored to the target structure and include intra-articular, perineural, intramuscular, and intrathecal approaches.^1,2

Overall, injectable agents remain a cornerstone of non-operative management for a range of musculoskeletal and neurologic disorders, with ongoing research refining their indications, efficacy, and safety profiles.^1-11

Commonly used peripheral agents include corticosteroids, local anesthetics, hyaluronic acid, platelet-rich plasma (PRP), autologous conditioned serum (ACS), and prolotherapy solutions. Intrathecally administered medications include opioids, baclofen, clonidine, and ziconotide. These agents act via diverse mechanisms: corticosteroids and hyaluronic acid modulate inflammation and joint homeostasis; local anesthetics stabilize neuronal membranes; opioids, baclofen, clonidine, and ziconotide provide receptor-mediated analgesia or spasticity control; PRP and ACS promote tissue healing and regeneration.^3-7

Recent advances in ultrasound guidance have significantly improved the accuracy and safety of joint, tendon, bursal, and peripheral nerve injections. Ultrasound guidance is superior to landmark-based techniques for deep or anatomically complex targets, with higher accuracy rates and reduced risk of complications.^8,9 This has led to widespread adoption of ultrasound-guided injections in clinical practice.

The following table summarizes the most common injectable agents used in musculoskeletal and neurologic conditions, their primary indications, administration route, and mechanism of action. Additionally, supporting evidence from recent reviews and consensus guidelines are included where possible. (Table 1)

Table 1 – Injectable Agents, Indications, Route of Administration, and Mechanism of Action

Relevance to Clinical Practice

Corticosteroids

The most common medications used for injection therapy to treat musculoskeletal pain are corticosteroids, typically administered in combination with local anesthetics.^1,3 Injectable corticosteroids for musculoskeletal conditions are classified by their solubility and particulate nature, which directly influence onset, duration, and safety profiles.

Particulate corticosteroids—including triamcinolone acetonide, triamcinolone hexacetonide, methylprednisolone acetate, and betamethasone acetate—are hydrophobic and form crystalline suspensions. These agents have slower onset but longer duration of anti-inflammatory effect due to lower solubility and prolonged tissue retention. Triamcinolone hexacetonide is the least soluble and provides the longest duration of action, while methylprednisolone acetate and betamethasone acetate are intermediate.^12-13 Triamcinolone preparations are the most frequently used corticosteroids and are approved for intra-articular use by both the FDA and in Europe.¹². Particulate steroids are preferred for intra-articular injections where prolonged effect is desired, However, these medications carry risk of skin hypopigmentation and soft tissue atrophy. With spinal epidural injections, particulate steroids are often avoided, due to potential for rare but catastrophic embolic complications.¹⁴

Non-particulate corticosteroids— limited to dexamethasone and betamethasone sodium phosphate—are water-soluble, with comparatively rapid onset and shorter duration of action relative to particulate steroids. These agents are considered safer for higher-risk procedures, such as epidural injections, but may require more frequent dosing for sustained effect.^12-14

Dosing is individualized based on joint size and agent selected. For large joints, 20–40 mg of triamcinolone acetonide or methylprednisolone acetate is commonly used; for smaller joints, 10–20 mg is standard. Betamethasone preparations are dosed lower due to higher potency, with typical intra-articular doses ranging from 2–6 mg.^12-13 Most sports medicine physicians use triamcinolone or methylprednisolone, often diluted with lidocaine, and total injectate volumes of 5–7 mL for large joints.¹³

Comparative efficacy data are limited. Available randomized trials and systematic reviews suggest triamcinolone hexacetonide may provide faster and more durable pain relief than methylprednisolone or betamethasone for some indications, though long-term efficacy is similar across agents.^1,4 For soft tissue injections, methylprednisolone and triamcinolone acetonide are commonly used, with no clear superiority.^15,16

The standard approximate doses for intraarticular injections are outlined in Table 2.

Table 2. Corticosteroid Suspensions for Intra-articular Injection

*Typical dose injected varies depending on joint size, medical comorbidities, and patient age

Table 2 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 follows¹⁷

• Skin infection overlying injection site
• Broken skin at injection site
• Septic arthritis/bursitis
• Osteomyelitis
• 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^18,19

• 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.^18,19 Alteration of menses following corticosteroid administration can occur due to hypothalamic-pituitary axis estradiol suppression.²⁰

Local anesthetics

The two most frequently 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 intra-articular (IA) injections, it is recommended to administer no more than 100 mg in 5 ml or 10 ml aliquots.^21,22

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. Physicians should strictly calculate maximum doses based on the patient’s total body weight in kilograms.^22,23

Local anesthetic systemic toxicity (LAST) can present with symptoms of central nervous system excitation, including, but not limited to the following

• Nervousness
• Tingling around the mouth
• Tinnitus
• Tremor
• Dizziness
• 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. The symptoms of LAST do not always have focal deficits first; occasionally symptoms may present as systemic. Bupivacaine has the potential to cause toxicity at much lower dosages than lidocaine because of its increased fat solubility. Furthermore, bupivacaine is more cardiotoxic due to its increased affinity for cardiac sodium ion channels.

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.²¹ These studies used 10mL of different concentrations of local anesthetic; chondrotoxic effects were worse with increased time of exposure and dose of local anesthetic. Thus, the least amount of local anesthetic should be used to treat painful joints. Furthermore, several studies suggest local anesthetics such as lidocaine and bupivacaine have chondrotoxic effects that are worsened by co-administration with corticosteroids.^22,23

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.^24,25

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 the post-injection period lasts 5 to 13 weeks. As a result, pain was improved from 28 to 54%, and function was improved from 9 to 32% from baseline. A comparison with NSAIDs showed comparable efficacy and a longer-term benefit when compared to IA corticosteroids. These analyses found that hyaluronan/hylan trials generally had few adverse events.²⁵

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.^24-27

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.^25-26 Similarly, HA has been shown to be effective in shoulder arthritis, though with unclear benefit compared to corticosteroid injection.^25-27 Studies for HA in hip arthritis have been less promising, where existing studies show no superiority when compared to placebo.²⁸

Intrathecal baclofen

Baclofen is a centrally acting muscle relaxant which demonstrates GABA B receptor agonism. It can be administered both orally or intrathecally. Baclofen’s adverse effects include flaccidity, weakness, constipation, urinary retention, sedation, and hypotension. Baclofen overdose can lead to respiratory depression, seizures, and death.²⁹Abrupt 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.²⁹ Symptoms of Baclofen withdrawal include the following

• Anxiety
• Hallucinations
• Pruritus
• Fever
• Tachycardia
• Labile blood pressure
• Muscle rigidity
• Death

Intrathecal baclofen (ITB) therapy is a well-established intervention for refractory lower extremity spasticity and associated chronic pain of both spinal and cerebral origin. The American Academy of Physical Medicine and Rehabilitation, in its 2024 consensus guidance, affirms that ITB is effective for chronic spasticity due to spinal cord injury, multiple sclerosis, acquired brain injury, cerebral palsy, and stroke, especially in patients who have failed or cannot tolerate oral anti-spasticity agents. ITB allows for targeted delivery to spinal GABA receptors, minimizing systemic side effects and drug interactions compared to oral baclofen.³⁰ Recent research and consensus highlight that ITB should not be reserved solely as a last resort; it may be considered earlier in the treatment course for select patients to optimize function and reduce reliance on systemic medications. ³⁰ Candidates should undergo a screening trial (typically 50 mcg intrathecal bolus, titrated as needed) to assess response and tolerability prior to pump implantation. Dosing recommendations have been updated: maintenance doses typically range from 300–800 mcg/day for spinal origin and 90–700 mcg/day for cerebral origin, with individual titration required.Dose adjustments are made in 5–40% increments based on clinical response and side effects.^30-31

Long-term safety outcomes and complication rates have been further characterized in recent studies. The most common complications are catheter malfunction (up to 14%), pump malfunction (7.3%), and infection (6%), with overall complication rates around 27% in adults; risk increases with time since implantation and is influenced by ambulatory status and body mass index. ^32-33 In pediatric and young adult populations, catheter complications and pseudomeningoceles are most frequent, but newer catheter models and improved surgical techniques have reduced these risks. ITB therapy consistently demonstrates significant reductions in spasticity (Modified Ashworth Scale), spasm frequency, and pain, with improvements in mobility and quality of life.³⁴

In summary, ITB pump therapy is supported by recent consensus and clinical data as an effective, programmable, and customizable option for refractory lower extremity spasticity and chronic pain, with individualized dosing and a well-characterized safety profile.^30-34

Opioids

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 rexed 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 dorsal root ganglion. Morphine may also inhibit the release of excitatory neurotransmitters from nerve terminals carrying nociceptive stimuli.²⁹

Morphine is the criterion standard for intrathecally administered analgesics and is the only opioid Food and Drug Administration (FDA) approved for intrathecal use.²⁹ Other opioids, such as hydromorphone, fentanyl, sufentanil, methadone, and buprenorphine, and another controlled substance, midazolam, have been used in clinical trials.³⁵ 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.This may be related to opioid infusion concentration. These can be large enough to cause neurologic dysfunction and cord compression.^29,35

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.³⁵ 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.³⁵

Other

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 excitatory neurotransmitters that relay pain signals.³⁶ Clonidine is the only alpha-2 agonist FDA approved for intrathecal use.²⁹ Caution must be exercised in individuals who have hypotension. Abrupt discontinuation of intrathecal clonidine can result in rebound hypertension.²⁹ Side effects of clonidine include but not limited to the following:

• Dry mouth
• Nausea
• Dizziness
• Confusion
• Sedation
• Bradycardia
• Hypotension

Ziconotide is a synthetic venom peptide derived from a cone snail species, Conus magus, which functions by blocking type N-presynaptic calcium channels in the dorsal horn of the spinal cord. This medication can be used for patients with neuropathic pain that is resistant to systemic pre-trial opioid therapy.²⁹ This drug is also advantageous for analgesia when used via IT because it does not cause respiratory depression and can be used in low dosages.  However, Ziconotide has a narrow therapeutic window, which makes it difficult to manage. Ziconotide should be titrated slowly to reduce side effects. Psychosis and suicidal ideation are associated with rapid titration. Adverse effects on CNS include ataxia, nystagmus, nausea, dysmetria, agitation, dizziness, hallucinations, and coma. There is no withdrawal or rebound effect caused by the sudden interruption.²⁹ When psychiatric changes or kidney disease are not present, ziconotide is recommended as the first option for IT pump therapy.²⁹

Cutting Edge/Unique Concepts/Emerging Issues

PRP (platelet-rich plasma) is considered the latest trend in nonoperative musculoskeletal care. PRP is most simply defined as a volume of plasma that has a platelet count above baseline blood levels. To extract platelet-rich plasma, a small volume of whole blood is withdrawn from the patient, centrifuged, and then diluted. There is then a layer of concentrated platelets that can be collected for further use. The platelets, when reinjected back into the patient (joint, tendon, ligament, muscle, 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. Chemical mediators such as growth factors orchestrate the body’s own natural healing process, resulting in stronger, more organized, normative tissue.³⁷ As a result, the old abnormal tissue is replaced by the newly formed healthier tissue.

PRP’s main drawback is there is no standard method for production or quality measures. There exist four main categories of PRP, which 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).⁴¹ 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.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.⁴¹

Multiple randomized controlled trials and consensus guidelines from the American Society of Pain and Neuroscience support PRP as superior to corticosteroids and hyaluronic acid for pain relief and functional improvement in knee osteoarthritis, with benefits sustained up to 12–24 months.^38-40 PRP is also effective for chronic low back pain and discogenic pain, with long-term improvements in pain and function.^42-43 Ongoing advances in PRP preparation and delivery are improving consistency and efficacy, and combination therapies are under investigation.^39,44,45

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.⁴⁶ 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. The pain reduction between ACS compared to HA and saline were statistically significant with P value P < 0.001 for each comparison.⁴⁶

More recently, there have been several 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.⁴⁷ 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).  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.⁴⁷ 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 A is a neurotoxin produced by Clostridium botulinum.²⁸ The U.S. Food and Drug Administration approved BoNT/A for its muscle paralyzing effects in neuromuscular disorders, such as spasticity, cervical dystonia, and blepharospasm.²⁸ Recent reviews and clinical studies continue to support its expanding role in pain management, including myofascial pain, chronic migraine, and refractory bladder pain. In a recent study, OnabotulinumtoxinA demonstrated sustained efficacy for myofascial trigger points, with superior outcomes at 3 and 6 months compared to PRP and local anesthetic for masseter muscle pain.⁴⁸ Its mechanism involves both neuromuscular blockade and anti-inflammatory effects, and emerging research is exploring combination therapies and personalized dosing strategies to optimize outcomes.^49-50 FDA-approved indications remain unchanged, but off-label use in chronic pain management and regenerative medicine is increasing.^49-53

Prolotherapy is a procedure in which a substance, typically hypertonic dextrose, is injected into a joint or tendon to stimulate a controlled, local inflammatory response and promote growth of normal. 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 regarding KOOS scores (P<0.001).⁵⁴ 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.^14-18

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 Quervain’s tenosynovitis.^55-57 Further research is needed on whether intraarticular injections with image guidance improves osteoarthritis treatment efficacy.⁵⁸ 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.⁵⁸ 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.⁵ 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.⁵⁹

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Original Version of the Topic

Armando S. Miciano, MD, Jonas Sokolof, DO, Devi Nampiaparampil, MD. Injectable agents. 9/20/2013.

Previous Revision(s) of the Topic

McCasey Smith, MD, MS, David Sherwood, DO, Lauren Neuman, DO, Stephen Bai, MD, Anthony Jackson, MD, Derek Schirmer, DO. Injectable agents. 9/24/2019.

Casey A. Murphy, MD, Richard Fontanez, MD. Injectable Agents. 11/30/2022

Author Disclosure

William W. White Jr., DO
Nothing to Disclose

Andrew P. Boyer, DO
Nothing to Disclose