Injectable agents

Author(s): Armando S. Miciano, MD, Jonas Sokolof, DO, Devi Nampiaparampil, MD

Originally published:09/20/2013

Last updated:09/20/2013

1. OVERVIEW AND DESCRIPTION

Injectable agents are often used diagnostically and/or therapeutically to address musculoskeletal or associated nerve problems in peripheral joints, trigger points, bursae, or tendon sheath (Table 1).1

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

Opioid

X

X

X

Baclofen

X

Clonidine

X

Ziconotide

X

Platelet-rich plassma

X

Autologous conditioned serum

X

Botulinum toxin X

X

Musculoskeletal problems most frequently encountered in injection practices involve the knees, trochanteric bursae, and glenohumeral joints.2 Trigger point injections address regional pain syndromes, including myofascial pain, low back/neck pain, and headache.3 Common peripheral nerve blocks are often done on the suprascapular nerve, lateral femoral cutaneous nerve, and femoral nerve, as well as for spasticity and neuropathic pain.Intrathecal systems are used for long-term management in malignancy, neuropathic, or chronic pain6 or in spastic hypertonia caused by cerebral palsy, spinal cord injury, or brain injuries.4

Many practitioners do not use any image guidance for most peripheral injections. A 10% to 40% miss rate of blind injections exists when compared with guided injections.1 Guidance should be considered for near-neurovascular structures, nonsuperficial structure, or inadvertent injection of nontargeted tissues.1,5

Local anesthetics are membrane-stabilizing drugs, acting mainly by inhibiting voltage-gated sodium channels in the neuronal cell membrane.2,4

They are often used in combination with corticosteroids. The first description of intraarticular corticosteroid injection demonstrated clinical improvement with the injection of hydrocortisone in patients with inflammatory joint conditions.1 The anti-inflammatory properties of corticosteroids are the result of 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

Corticosteroid duration of action depends on the preparation. The ester and amide classes of anesthetics differ in action onset, potency, and duration. The addition of sodium bicarbonate and epinephrine prolongs the action. Increasing the dose shortens action onset and increases potency and duration.1,4

Indications for intraspinal analgesics include chronic pain with known pathophysiology, sensitivity of pain to medication being used, failure of conservative therapy, favorable psychosocial evaluation, and favorable trial response.1,6

Delivery of agents directly to opioid receptors was noted to decrease the systemic effects of the medications and dosage needed to achieve analgesia.1 Opioids, administered neuraxially, act at substantia gelatinosa receptors through inhibition of presynaptic neurotransmitter release and postsynaptic neuronal hyperpolarization.6

Another drug that can be administered neuraxially is baclofen. It is used for intractable spasticity, resistant to tolerable doses of oral medication. The patient and family must be committed to the long-term follow-up care required.1

Intrathecal baclofen allows a 100-fold increase in potency, with little brain exposure to medication and without significant sedating side effects.1Baclofen is a GABA-B agonist, decreases excitatory amino acid release, and inhibits the release of substance P.6

2. RELEVANCE TO CLINICAL PRACTICE

The most common medications used for injection therapy to treat musculoskeletal pain are local anesthetics and corticosteroids.7 The most commonly used injectable corticosteroid used in the United States for musculoskeletal pain is methylprednisolone. Other frequently used agents include: betamethasone sodium phosphate/acetate, triamcinolone acetonide, and triamcinolone hexacetonide. These corticosteroids range in solubility, which directly influences action duration (Table 2). 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

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.

Contraindications for corticosteroid injection are as follows:

  1. Skin infection overlying injection site
  2. Broken skin at injection site
  3. Known hypersensitivity to corticosteroid agent
  4. Prosthetic joint
  5. Osteochondral/intraarticular fracture
  6. Severe joint destruction
  7. Unstable coagulopathy7

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:

  1. Cutaneous atrophy at injection site
  2. Tendon and ligament rupture
  3. Calcification of soft tissue structures8,9

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, because injected corticosteroids can affect the hypothalamic-pituitary axis.

The 2 most commonly used local anesthetics are lidocaine and bupivacaine. Lidocaine is a short-acting amino amide local anesthetic with rapid onset and short duration. Bupivacaine, also an amide, has a longer onset and duration. Contrary to corticosteroids, local anesthetics have a higher potential for adverse systemic effects; the risk rapidly escalates with higher dosages. Local anesthetic toxicity can present as central nervous system excitation such as:

  1. Nervousness
  2. Tingling around the mouth
  3. Tinnitus
  4. Tremor
  5. Dizziness
  6. Blurred vision8,9

Once toxicity has progressed, seizures followed by loss of consciousness and respiratory depression can develop. Cardiovascular effects include hypotension, bradycardia, arrhythmias, and cardiac arrest. Bupivaine has the potential to cause toxicity at much lower dosages than lidocaine because of its increased solubility and is considerably more cardiotoxic. Physicians should monitor dosages and not exceed the maximum delivery dose based on the patient’s body weight.8,9

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 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:

  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

4. 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 in turn release growth factors, such insulin-like growth factor 1, vascular endothelial growth factor, platelet-derived growth factor, among several others. These growth factors serve as chemical mediators to orchestrate the body’s own natural healing response. The end result is the formation of stronger, more organized, normative appearing scar tissue. The new now healthier tissue takes the place of the old abnormal tissue. A recent meta-analysis determined that there is a considerable paucity of high quality trials to support the use of PRP in the clinical setting.11 However, new data on the treatment of chronic tennis elbow are encouraging. 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.12,13

Autologous conditioned serum 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 serum 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.

Botulinum toxin based on its postulated antinociceptive and anti-inflammatory effects has also been recently studied as an injectable agent to treat joint pain. One study shows similar efficacy to intraarticular steroids.14

5. GAPS IN KNOWLEDGE/EVIDENCE BASE

Further research is needed on whether intraarticular injections with image guidance improves osteoarthritis treatment efficacy.5 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

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.

Bibliography

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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.

Author Disclosure

Armando S. Miciano, MD
Nothing to Disclose

Jonas Sokolof, DO
Nothing to Disclose

Devi Nampiaparampil, MD
Nothing to Disclose

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