Injectable Agents

Author(s): McCasey Smith, MD, MS, David Sherwood, DO, Lauren Neuman, DO, Stephen Bai, MD, Anthony Jackson, MD, Derek Shirmer, DO candidate

Originally published:09/20/2013

Last updated:09/24/2019

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.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

Intrathecal Intramuscular Intravenous Perineural Intraarticular
Local anesthetic X X X X
Corticosteroid X X X X X
Botulinum Toxin X
Hyaluronic Acid X
Opioid X X X
Baclofen X
Clonidine X
Ziconotide X

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

Corticosteroids

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)
Hydrocortisone acetate 0.002
Methylprednisolone acetate 0.001
Prednisolone tebutate 0.001
Triamcinolone acetate 0.004
Triamcinolone hexacetonide 0.0002

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)
Hydrocortisone tebutate 50 25-100
Bethamethasone acetate and sodium phosphate 6 1.5-6
Methylprednioslone acetate 20 4-40
Triamcinolone acetonide 40 5-40
Triamcinolone diacetate 40 5-40
Triamcinolone hexactonide 20 5-40

*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

  1. Skin infection overlying injection site
  2. Broken skin at injection site
  3. Septic arthritis/bursitis
  4. Osteomyelitis
  5. Febrile illness
  6. Systemic bacteremia
  7. Known hypersensitivity to corticosteroid agent
  8. Unstable Joint
  9. Prosthetic joint
  10. Osteochondral/intraarticular fracture
  11. Severe joint destruction
  12. 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

  1. Post-procedure pain
  2. Subcutaneous atrophy at injection site
  3. Skin depigmentation
  4. Tendon and ligament rupture
  5. 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

Local Anesthetics

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

  1. Nervousness
  2. Tingling around the mouth
  3. Tinnitus
  4. Tremor
  5. Dizziness
  6. 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

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:

  1. Anxiety
  2. Hallucinations
  3. Pruritus
  4. Fever
  5. Tachycardia
  6. Labile blood pressure
  7. Muscle rigidity
  8. Death6

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

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

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 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:

  1. Dry mouth
  2. Nausea
  3. Dizziness
  4. Confusion
  5. Sedation
  6. Bradycardia
  7. Hypotension6

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

REFERENCES

  1. Braddom RL. Physical Medicine and Rehabilitation. 4th ed. Philadelphia, PA: Elsevier; 2011.
  2. Wittich CM, Ficalora RD, Mason TG, Beckman TJ. Musculoskeletal injection. Mayo Clin Proc. 2009;84:831-836.
  3. Annaswamy TM, De Luigi AJ, O’Neill BJ, Keole N, Berbrayer D. Emerging concepts in the treatment of myofascial pain: a review of medications, modalities, and needle-based interventions. PM R. 2011;3:940-961.
  4. Manchikanti L, Singh V, Kloth D, et al. Interventional techniques in the management of chronic pain: Part 2.0. Pain Physician. 2001;4:24-98.
  5. Hameed F, Ihm J. Injectable medications for osteoarthritis. PM R. 2012;4(5 Suppl):S75-S81.
  6. Smith HS, Deer TR, Staats PS, Singh V, Sehgal N, Cordner H. Intrathecal drug delivery. Pain Physician. 2008;11(2 Suppl):S89-S104.
  7. Stephens MB, Beutler AI, O’Connor FG. Musculoskeletal injections: a review of the evidence. Am Fam Physician. 2008;78:971-976.
  8. Lavelle W, Lavelle ED, Lavelle L. Intra-articular injections. Med Clin North Am. 2007;91:241-250.
  9. Snibbe JC, Gambardella RA. Use of injections for osteoarthritis in joints and sports activity. Clin Sports Med. 2005;24:83-91.
  10. Hayek SM, Deer TR, Pope JE, Panchal SJ, Patel VB. Intrathecal therapy for cancer and non-cancer pain. Pain Physician. 2011;14:219-248.
  11. Sheth U, Simunovic N, Klein G, et al. Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a meta-analysis. J Bone Joint Surg Am. 2012;94:298-307.
  12. 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.
  13. Mishra A, et al. Platelet rich plasma significantly improves clinical outcomes in patients with chronic tennis elbow. Am J Sports Med. In Press.
  14. 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.
  15. 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
  16. Anderson S, Krug H, Dorman C, McGarraugh P, Frizelle S, Mahowald M. Analgesic effects of intra-articular botulinum toxin type B in a murine model of chronic degenerative knee arthritis pain. J Pain Res. 3(2010) 161-16
  17. Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and other cure options. Eur J Neurol, 11 (2004) 361-370
  18. Heikkila HM, Hielm-Bjorkman AK, Morelius M, Larsen S, Honkavaara J, Innes JF. Intra-articular botulinum toxin A for the treatment of osteoarthritic joint pain in dogs: a randomized, double-blinded, placebo controlled clinical trial. Vet J, 200 (2014)162-169
  19. Mahowald ML, Krug HE, Singh JA, Dykstra D. Intra-articular botulinum toxin type A: a new approach to treat arthritis joint pain. Toxicon. 2009 54;658-667
  20. Daniels, E. W., Cole, D., Jacobs, B., & Phillips, S. F. (2018). Existing Evidence on Ultrasound-Guided Injections in Sports Medicine. Orthopaedic Journal of Sports Medicine, 6(2), 232596711875657.doi:10.1177/2325967118756576
  21. Jones, I. A., Togashi, R., Wilson, M. L., Heckmann, N., & Vangsness, C. T. (2018). Intra-articular treatment options for knee osteoarthritis. Nature Reviews Rheumatology.doi:10.1038/s41584-018-0123-4
  22. Andia, I. & Maffulli, N. Platelet- rich plasma for managing pain and inflammation in osteoarthritis. Nat. Rev. Rheumatol. 9, 721–730 (2013).
  23. Hepper, C.T.; Halvorson, J.J.; Duncan, S.T.; Gregory, A.J.; Dunn, W.R.; Spindler, K.P. The efficacy and duration of intra-articular corticosteroid injection for knee osteoarthritis: A systematic review of level I studies. J. Am. Acad. Orthop. Surg. 2009, 17, 638–646.
  24. Paik, Julia et al. “Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee.” Drugs vol. 79,4 (2019): 455-462.
  25. Jayaram P, Kennedy DJ, Yeh P, Dragoo J. Chondrotoxiceffects of local anesthetics on human knee articular cartilage: A systematic review. PM R. 2019;11:379–400.
  26. Evans, CH, Kraus, VB, Setton, LA. Progress in intra-articular therapy. Nat Rev Rheumatol 2014; 10: 11–22.
  27. Ayhan E, Kesmezacar H, Akgun I. Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis. World J Orthop. 2014;5(3):351–361. Published 2014 Jul 18. doi:10.5312/wjo.v5.i3.351
  28. Wehling P, Evans C, Wehling J, Maixner W. (2017). Effectiveness of intra-articular therapyies in osteoarthritis: a literature review. Therapeutic Advances in Musculoskeletal Disesase, 183-196. https://doi.org.10.1177/1759720X17712695
  29. Saunders, S. (. t., & Longworth, S. (2019). Injection techniques in musculoskeletal medicine: A practical manual for clinicians in primary and secondary care(Fifth edition.). Edinburgh: Elsevier.
  30. Bellamy N, Campbell J, Welch V, Gee TL, Bourne R, Wells GA. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No. CD005321. DOI: 10.1002/14651858. CD005321.
  31. Miller, R. D. (2010). Miller’s anesthesia(7th ed.). Philadelphia, PA: Churchill Livingstone/Elsevier.
  32. Cole, Brian J., et al. Orthobiologics in Sports Medicine. Elsevier, 2019.
  33. Walsh N, Eckmann M. Pharmacology for the Interventional Pain Physician. In: Gans B, Walsh N, Robinson L, eds. Delisa’s Physical Medicine & Rehabilitation: Principles and Practice. 5thPhiladelphia, PA: Lippincott Williams & Wilkins; 2010:1852-1854.
  34. Han, Yanhong et al. “Meta-analysis Comparing Platelet-Rich Plasma vs Hyaluronic Acid Injection in Patients with Knee Osteoarthritis.” Pain medicine (Malden, Mass.), vol. 20,7 1418–1429. 7 Mar. 2019, doi:10.1093/pm/pnz011
  35. Pourcho AM, Smith J, Wisniewski SJ, et al. Intraarticular platelet-rich plasma injection in the treatment of knee osteoarthritis: review and recommendations. Am J Phys Med Rehabil 2014; 93: S108–S121.
  36. A.W.A. Baltzer, C. Moser, S.A. Jansen, R. Krauspe, Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis, Osteoarthritis and Cartilage, Volume 17, Issue 2, 2009, Pages 152-160, ISSN 1063-4584, https://doi.org/10.1016/j.joca.2008.06.014.
  37. Dohan Ehrenfest, David M et al. “Classification of platelet concentrates (Platelet-Rich Plasma-PRP, Platelet-Rich Fibrin-PRF) for topical and infiltrative use in orthopedic and sports medicine: current consensus, clinical implications and perspectives.” Muscles, ligaments and tendons journalvol. 4,1 3-9. 8 May. 2014
  38. 38. Paik, J., Duggan, S.T. & Keam, S.J. Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee. Drugs (2019) 79: 455. https://doi.org/10.1007/s40265-019-01083-3
  39. Buchbinder R, Green S, Youd JM. Corticosteroid injections for shoulder pain. Cochrane Database of Systematic Reviews 2003, Issue 1. Art. No.: CD004016. DOI: 10.1002/14651858.CD004016
  40. Kearney RS, Parsons N, Metcalfe D, Costa ML. Injection therapies for Achilles tendinopathy. Cochrane Database of Systematic Reviews 2015, Issue 5. Art. No.: CD010960. DOI: 10.1002/14651858.CD010960.pub2
  41. Peters-Veluthamaningal C, van der Windt DAWM, Winters JC, Meyboom-de Jong B. Corticosteroid injection for de Quervain’s tenosynovitis. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD005616. DOI: 10.1002/14651858.CD005616.pub2
  42. Bloom JE, Rischin A, Johnston RV, Buchbinder R. Image-guided versus blind glucocorticoid injection for shoulder pain. Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD009147. DOI: 10.1002/14651858.CD009147.pub2
  43. Ammendolia C, Stuber KJ, Rok E, Rampersaud R, Kennedy CA, Pennick V, Steenstra IA, de Bruin LK, Furlan AD. Nonoperative treatment for lumbar spinal stenosis with neurogenic claudication. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD010712. DOI: 10.1002/14651858.CD010712
  44. Hashemi SM, Maddi F, et al. Intra-articular hyaluronic acid injections Vs. dextrose prolotherapy in the treatment of osteoarthritic knee pain. Tehran Univ Med J. 2012; 70 (2) :119-125
  45. Legré-Boyer V. Viscosupplementation: techniques, indications, results. Orthop Traumatol Surg Res. 2015;101:S101–S108. doi:10.1016/j.otsr.2014.07.027.
  46. Gigante A, Callegari L. The role of intra-articular hyaluronan (Sinovial®) in the treatment of osteoarthritis. Rheumatol Int. 2011;31:427–444. doi: 10.1007/s00296-010-1660-6.
  47. Papalia R, Albo E, Russo F, Tecame A, Torre G, Sterzi S, Bressi F, Denaro V. The use of hyaluronic acid in the treatment of ankle osteoarthritis: a review of the evidence. J Biol Regul Homeost Agents. 2017 Dec 27;31(4 Suppl 2):91-102.
  48. 48. Zhang B, Thayaparan A, Horner N, Bedi A, Alolabi B, Khan M. Outcomes of hyaluronic acid injections for glenohumeral osteoarthritis: a systematic review and meta-analysis. J Shoulder Elbow Surg. 2019 Mar;28(3):596-606. doi: 10.1016/j.jse.2018.09.011.

Bibliography

Coffey RJ, Edgar TS, Francisco GE, et al. Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome. Arch Phys Med Rehabil. 2002;83:735-741.

DeLisa JA. Physical Medicine & Rehabilitation: Principles and Practice. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

Follett KA, Boortz-Marx RL, Drake JM, et al. Prevention and management of intrathecal drug delivery and spinal cord stimulation system infections. Anesthesiology. 2004;100:1582-1594.

Follett KA, Burchiel K, Deer T, et al. Prevention of intrathecal drug delivery catheter-related complications. Neuromodulation. 2003;6:32-41.

Francisco GE, Saulino MF, Yablon SA, Turner M. Intrathecal baclofen therapy: an update. PM R. 2009;1:852-858.

Hassenbusch S, Burchiel K, Coffey RJ, et al. Management of intrathecal catheter-tip inflammatory masses: a consensus statement. Pain Med. 2002;3:313-323.

Management of chronic pain syndromes: issues and interventions. Pain Med. 2005;6 Suppl 1:S1-S20.

Smith TJ, Staats PS, Deer T, et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol. 2002;20:4040-4049.

Original Version of the Topic

Armando S. Miciano, MD, Jonas Sokolof, DO, Devi Nampiaparampil, MD. Injectable agents. 09/20/2013.

Author Disclosure

McCasey Smith, MD, MS
Nothing to Disclose

David Sherwood, DO
Nothing to Disclose

Lauren Neuman, DO
Nothing to Disclose

Stephen Bai, MD
Nothing to Disclose

Anthony Jackson, MD
Nothing to Disclose

Derek Shirmer, DO candidate
Nothing to Disclose

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