Injections for Chronic Pain

Virtaj Singh, MDa,*, Andrea Trescot, MDb, Isuta Nishio, MDc

KEYWORDS

� Chronic pain � Regenerative injections � Trigger point injections � Botulinum toxins

KEY POINTS

� Even in the setting of chronic pain, various injections can still have a useful role infacilitating a rehabilitation program.

� Spinal injections, such as epidural steroid injections and facet joint injections, are amongthe most commonly used procedures in most pain practices; but a growing number ofpractices are considering less common injections, such as trigger point injections, regen-erative injections/prolotherapy, and injections using botulinum toxins.

INTRODUCTION

Although interventional procedures should be used cautiously in the setting of chronicpain, there is a role for a variety of injections to facilitate patients’ overall rehabilitationprogram. There are many resources available, including a prior edition of Physical Med-icine and Rehabilitation Clinics of North America, which discuss the more conventionalspinal injections. The focus of this article is on lesser-known injection options for treatingchronic pain. The authors separately discuss trigger point injections (TPIs), regenerativeinjections (prolotherapy), and injections using botulinum toxins (BTx).

TRIGGER POINT INJECTIONS

Myofascial pain syndrome (MPS) is a common musculoskeletal pain syndrome char-acterized by a myofascial trigger point (MTrP) at muscle, fascia, or tendinous inser-tions. A MTrP is a hyperirritable tender spot, frequently associated with taut bandthat, on palpation, is firmer in consistency than adjacent muscle fibers. When com-pressed, an MTrP may cause patient vocalization or a visible withdrawal (which isknown as the jump sign).

a Department of Rehabilitation Medicine, Seattle Spine & Sports Medicine, University ofWashington, 3213 Eastlake Avenue East, Suite A, Seattle, WA 98102, USA; b Pain and HeadacheCenter, 5431 Mayflower Lane, Suite 4, Wasilla, AK 99654, USA; c Department of Anesthesiologyand Pain Medicine, VA Puget Sound Health Care System, University of Washington, 1660 SouthColumbian Way, S-112-Anes, Seattle, WA 98108, USA* Corresponding author.E-mail address: vsingh@seattlespine.com

Phys Med Rehabil Clin N Am 26 (2015) 249–261http://dx.doi.org/10.1016/j.pmr.2015.01.004 pmr.theclinics.com1047-9651/15/$ – see front matter � 2015 Elsevier Inc. All rights reserved.

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Stretching and exercise are the foundation of treatment and management of MPS;however, for refractory cases, needle therapy may be offered. This therapy mayinclude TPIs (using local anesthetics, corticosteroids, and/or BTx), dry needling (DN)(intramuscular stimulation [IMS]), and acupuncture.

Local Anesthetics

Despite the popularity of TPIs, there is no conclusive evidence that demonstratessuperior effectiveness of TPIs over DN in the treatment of MPS.1,2 One systematic re-view of randomized controlled trials found that direct injection to MTrPs was indeedeffective but that the nature of the injected substance did not influence the outcome;hence, the investigators concluded that the beneficial effects of TPIs were likely theresult of needle insertion or placebo.1 However, another review showed short-termbenefits of TPIs with lidocaine that were superior to DN or placebo.3 It is conceivablethat local pain and soreness associated with needling can be ameliorated with localanesthetic injection.2

Corticosteroids

Although inflammation may play a role inMPS, there is no evidence that the injection ofcorticosteroid provides any enhanced benefits.4 In addition, corticosteroids carry therisk of local muscle necrosis and adrenal suppression. Thus, the use of corticosteroidsfor TPIs is not recommended.

Botulinum Toxin

Botulinum toxin (BTx) is a potent neurotoxin produced by the bacterium Clostridiumbotulinum that blocks acetylcholine release into the neuromuscular junction, leadingto prolonged muscle relaxation (typically lasting 3 to 4 months). BTx is used for a va-riety of pain procedures as discussed separately in this article later. Briefly, the authorsdiscuss the use of BTx in TPIs.In TPIs, BTx is thought to reduce muscular ischemia and free entrapped nerve end-

ings. Central and peripheral antinociceptive properties of BTx have also been postu-lated. Despite these mechanisms that could theoretically offer a benefit for patientswith MPS, the use of BTx injections for myofascial trigger points is controversial.Meta-analyses of randomized trials in patients with neck pain have found no benefitof BTx intramuscular injections in the short-term (4 weeks) or long-term (6 months)when compared with placebo.5,6 Although a recent review7 showed inconclusive ev-idence regarding the effectiveness of BTx in the treatment of MPS, an older Cochranereview found moderate evidence that BTx injections are not effective.3 In sum, giventhe high cost of the medication and questionable evidence for its efficacy, cost andclinical value should be carefully assessed before considering BTx injections for MPS.

Dry Needling

Dry needling (DN) (also known as intramuscular stimulation [IMS]) involves the practiceof using a small-gauge needle (sometimes acupuncture needles) to irritate the MTrPwithout injecting any substance (as opposed to those discussed earlier). Systemic re-views and meta-analyses of randomized controlled trials suggest that DN is an effec-tive therapy for MPS.1,8,9 If DN is used to specifically target MTrPs, it is most effectivewhen a local twitch response (LTR) (brisk contraction of the taut band) is elicited.10 Afast-in-fast-out technique has been advocated to elicit a maximal number of LTRs.The needle penetrates the taut band of the muscle, is withdrawn to superficial subcu-taneous tissue, then redirected to another area in proximity (Fig. 1). Deep DN to the

Taut band Trigger point regionTrigger point locus

Fig. 1. TPIs and DN to myofascial trigger point. (Courtesy of Isuta Nishio, MD.)

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muscle (eg, 15 mm) has been shown to be more effective than superficial DN (eg,2 mm).11

Acupuncture

Acupuncture is an increasingly popular treatment of a broad spectrum of chronicconditions, including chronic pain. However, the number of needles used, the fre-quency of sessions, stimulation frequency, and current amplitude to obtain optimal ef-ficacy remains a matter of debate. A Cochrane review found that, in the short-term,acupuncture is more effective for chronic low back pain and neck pain compared tono treatment or sham acupuncture.12 Other meta-analyses have also demonstratedthe effectiveness of acupuncture for chronic pain when compared with no acupunc-ture or sham (needles placed in non-acupucture sites).13,14

The data suggest that the benefits of acupuncture are clinically relevant and greaterthan placebo; however, the observed differences in effectiveness between acupunc-ture and sham acupuncture are smaller than those between acupuncture and noacupuncture. This pattern of findings indicates that the nonspecific physiologic andpsychological effects of needling may be more important than the actual acupuncturetechnique itself.14,15

Needing Therapy: Mechanism of Action

The exact mechanism by which DN relieves MTrP and MPS has yet to be fully eluci-dated. DN has been shown to diminish spontaneous electrical activity when LTR is eli-cited.16 Hong and Simons17 suggested that LTR or referred pain seems to bemediated through a spinal reflex in response to stimulation of a sensitive locus (noci-ceptor) that is in the vicinity of an active locus (motor end plate). Because DN is mosteffective when LTR is elicited,4 it is theorized that DN may relieve MTrP via inhibition ofdysfunctional activity in the motor end plate of the skeletal muscle motor neuron.Acupuncture has been used for various pain conditions in addition to MPS. There is

increasing evidence of correlations and similarities between MTrPs and acupuncturepoints in terms of their distribution and referred pain patterns.18,19 An electrophysio-logic study showed that some acupuncture points are indeed MTrPs.20 Acupunctureanalgesia seems to be a manifestation of integrative processes at different levels ofthe central nervous system (CNS).21 The gate control theory (Melzack and Wall22)may in part explain these processes; namely, the theory postulates that non-noxious sensory input (eg, touch, pressure, vibration) into the CNS can modulate

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pain perception by activating inhibitory interneurons.22 Furthermore, the possible roleof endogenous opioids has been implicated in both TPIs and acupuncture as theiranalgesic effects can be in part reversed by naloxone.23,24

Key Points

� There is no firm evidence that TPIs are superior to DN or acupuncture for MPS;however, TPIs with local anesthetic may offer additional benefits via relievingpain associated with soreness from the needling procedure itself.

� There is no strong evidence to support the use of corticosteroid or BTx in TPIs.� DN seems to be effective for MPS, especially when LTR is elicited.� Acupuncture seems to be effective for chronic pain, but nonspecific physiologicand psychological effects may play a significant role in its benefits.

� The mechanism of action in needling therapy seems to be multifactorial,including integrative CNS processes and endogenous opioid peptides.

REGENERATIVE INJECTIONS

Regenerative injection therapy (RIT) encompasses a spectrum of injection treatmentsdesigned to stimulate repair of damaged tissue. These injections range from prolother-apy (which provides a mild neurolytic effect followed by a complex restorative processwith biochemically induced collagen regeneration), to platelet-rich plasma ([PRP],which uses autologous blood that has been spun down to separate out the platelets),to even stem cells (which can be autologous or banked).In 1956, George Hackett25 introduced the term fibroproliferative therapy or prolo-

therapy, defined as “the rehabilitation of an incompetent structure by generation ofnew cellular tissue.”25 He proposed this new name because the term sclerotherapythat had been used previously implied scar formation rather than regeneration. Inthe same text, he published composite pain maps generated from ligaments and ten-dons, which have unfortunately remained largely unknown to the medical community(Fig. 2). Contemporary understanding of the basic science of regenerative medicine isthat the regenerative/reparative healing process consists of 3 overlapping phases: in-flammatory, proliferativewith granulation, and remodelingwith contraction (Fig. 3). Theregenerative and reparative stages extend beyond the proliferative stage. The termRITwas originally coined by Felix Linetskey, MD to replace the name prolotherapy; but au-thors have used both terms to describe any of the treatments described next.The first of these techniques, RIT/prolotherapy stimulates chemo-modulation of

collagen by repetitive induction of inflammatory and proliferative stages, which leadsto tissue regeneration and repair. As a result, the tensile strength, elasticity, mass, andload-bearing capacity of collagenous connective tissues increases. The proliferant,which can be any of a number solutions (including dextrose/lidocaine, dextrose/phenol/glycerin, sodium morrhuate, and pumice), creates an inflammatory reaction,thereby generating new tissue at the fibro-osseous junction. Hormones and multiplegrowth factors mediate this complex process. Fig. 4 shows rabbit tendon hypertrophyafter prolotherapy.26

The next technique, RIT/PRP relies on the injection of concentrated platelets thatrelease growth factors to stimulate recovery in nonhealing soft tissues. Autologousblood is collected and centrifuged; the portion that contains a high proportion of plate-lets is syphoned off and injected into the tendon and ligament attachments at theenthesopathy site.RIT/stem cell injection involves utilization of autologous adult pluripotent mesen-

chymal stem cells from an individual’s bone marrow or adipose tissue as the

Fig. 2. Example of Hackett pain patterns. (Courtesy of Felix Linetsky, MD.)

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proliferating solution. Alternatively, banked placental stem cells are beginning to comeonto the market, facilitating stem cell procurement.Indications for RIT are listed in Box 1. Appropriate presenting complaints are

diverse. These include occipital and suboccipital headaches; pain in the posteriormidline and paramedial cervical spine, the cervicothoracic spine, the thoracic spine,

Fig. 3. Stages of wound healing. (Courtesy of Andrea Trescot, MD.)

Fig. 4. Rabbit tendons after RIT (the left [L] is the untreated control and the right [R] is thetreated side); (A) is after 6 weeks and (B) is after 3 months. (Courtesy of Felix Linetsky, MD.)

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the thoracolumbar spine, the lumbar spine, the lumbosacral spine, the scapula, andthe shoulder regions; pain between the shoulder blades, in the low back, buttocks,sacroiliac, trochanteric areas, and any combination of the aforementioned complaints.The onset of pain may be sudden or gradual; the intensity, duration, and quality of

pain are variable but usually associated with a traumatic event. Physical examinationmay reveal postural abnormalities, functional asymmetries, as well as combinations ofkyphoscoliosis, flattening of cervical and lumbar lordosis, or arm and/or leg length dis-crepancies. Variable combinations of flexion/extension, rotation, lateral bending, and/

Box 1

Indications for RIT

1. Painful enthesopathies, tendinosis, or ligamentosis from overuse and occupational andpostural conditions known as repetitive motion disorders

2. Painful enthesopathies, tendinosis, or ligamentosis secondary to sprains or strains

3. Painful hypermobility, instability, and subluxation of the axial joints secondary to ligamentlaxity accompanied by restricted range of motion at reciprocal segments that improvetemporarily with manipulation

4. Vertebral compression fractures with a wedge deformity that exert additional stress on theposterior ligamento-tendinous complex

5. Recurrent painful rib subluxations at the costotransverse, costovertebral, andsternochondral articulations

6. Osteoarthritis, spondylosis, and spondylolisthesis

7. Postsurgical cervical, thoracic, and low back pain (with or without instrumentation)

8. Posterior column sources of nociception refractory to steroid injections, nonsteroidalantiinflammatory therapy, and radiofrequency procedures

9. Enhancement of manipulative treatment and physiotherapy

10. Internal disk derangement

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or contractions under load can provoke pain. By correcting the ligament laxity that cre-ates the anterior pressure on the disk (causing the disk to bulge posteriorly) and thefacet instability (which causes spondylosis and reflex muscle contracture, leading tonerve entrapment), the underlying process can be halted and potentially reversed.These regenerative injections can be, and have been used, to treat painful conditionsfrom head to toe (Fig. 5).

Splenius capitis

Levator scapulae

Triceps

Teres minor

Teres major

Sacrospinalis

Adductor minimus

Longissimus capitis

Interspinales

and lumborum

Iliocostalis lumborum

Gluteus medius

Gluteus minimus

Gluteus maximus originfrom sactrotuberous

ligament

Adductor magnus

to sacrotuberous ligamentBiceps femoris insertion

Quadratus femoris

Internal oblique

External oblique

Longissimus thoracis

Spinalis

Iliocostalis thoracis

Iliopsoas

Splenius cervicis

Iliocostalis cervicis

Semitendinosus

Biceps femoris

Semimembranosus

Coccygeus

Multifidus

Quadratus lumborum

inferiorSerratus posterior

InfraspinatusDeltoid

TrapeziusSupraspinatus

Rhomboids

Fig. 5. RIT injection sites. (Courtesy of Felix Linetsky, MD.)

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The exquisite tenderness at the fibro-osseous junction (enthesis) is the pertinentsubjective clinical finding. These areas of tenderness are identified and marked tobecome the site of infiltration with local anesthetic. The initial needle placement atthe fibro-osseous junction usually reproduces the pain, which temporarily worsensduring infiltration of the local anesthetic and typically subsides within a few secondsafter infiltration. Determination of abolishment or persistence of tenderness, plus thelocal or referred pain (which objectifies the finding of tenderness), concludes theclinical examination and becomes the basis for clinical diagnosis and further RIT pro-cedures. The proliferant (dextrose/lidocaine for prolotherapy, platelets for PRP, orstem cells) can be injected subsequently or (with the dextrose) at the same time.RIT has been the subject of multiple published articles, including systematic

reviews, randomized trials, and numerous nonrandomized publications, which includeprospective and retrospective clinical studies as well as case reports. In a systematicreview of prolotherapy injections for chronic low back pain,27 the investigatorsincluded 4 randomized trials28 that were considered high quality, with a total of 344patients. Two of the four studies showed significant differences between the treatmentand control groups with regard to the proportion of individuals who reportedmore than50% reduction in pain or disability; however, the results of these studies could not bepooled. In addition, in one study, co-interventions confounded independent evaluationof results. In the second study of the review, there was no significant difference inmean pain and disability scores between the groups. In the third study, there was littleor no difference between the groups with regard to the number of individuals who re-ported more than 50% improvement in pain and disability. Reporting only mean painand disability scores, the fourth study showed no difference between groups. The au-thors of this systematic review concluded that there was conflicting evidenceregarding the efficacy of prolotherapy injections in reducing pain and disability in pa-tients with chronic low back pain. They also concluded that, in the presence of co-in-terventions, prolotherapy injections were more effective than placebo injections, andwere yet more effective when both injections and co-interventions were controlledconcurrently. In addition, there is substantial evidence for the effectiveness of prolo-therapy from nonrandomized prospective and retrospective studies as well as casereports.29–41 In sum, the extant literature, although it does not offer convincing evi-dence as to the overall efficacy of prolotherapy, does offer moderate evidence toshow its effectiveness in select patients when used with appropriate technique andco-interventions.Contraindications to RIT include general contraindications that are applicable to all

injection techniques; specific contraindications for RIT are listed in Box 2. Complica-tions do occur with RIT (as with any injection treatment), but statistically they are rare.There were several serious injuries in the 1950s when untrained providers injectedtoxic agents into the spinal column.42–44 The most recent statistical data are from asurvey of 450 physicians who perform RIT/prolotherapy.45 Of the estimated 450,000patients treated (each with at least 3 visits and at least 10 sites of injection), therewere 29 incidences of pneumothorax, 2 of which required chest tube placement(risk of pneumothorax 5 1 per 18,333 injections). There were also 24 non–life-threat-ening allergic reactions; postdural puncture headaches,46 end plate fractures (afterintradiscal dextrose),47 sterile meningitis,48 and cervical spine injuries49 have alsobeen described.Although risk is inherent in any active intervention, regeneration of worn, frayed, and

lax ligaments and tendonsholds thepromiseof treating thecauseof thepain rather thanjustmasking it or ablating thenerves that innervate it. Through the useof thebody’s ownhealing power, RIT holds the promise of restoration of function and reduction in pain.

Box 2

Contraindications for RIT

General contraindications

Allergy to anesthetic solutions

Bacterial infection, systemic or localized to the region to be injected

Bleeding diathesis secondary to disease or anticoagulants

Fear of the procedure or needle phobia

Neoplastic lesions involving the musculature and osseous structures

Recent onset of a progressive neurologic deficit

Requests for large quantity of sedation and/or opioids before and after treatment

Severe exacerbation of pain or lack of improvement after local anesthetic blocks

Specific contraindications

Acute arthritis (septic, gout, rheumatoid, or posttraumatic with hemarthrosis)

Acute bursitis or tendonitis

Acute nonreduced subluxations, dislocations, or fractures

Allergy to injectable solutions or their ingredients, such as dextrose (corn), sodium morrhuate(fish), or phenol

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Key Points

� RIT encompasses a spectrum of injection treatments designed to stimulaterepair of damaged tissue.

� Contemporary understanding of thebasic science of regenerativemedicine is thatthe regenerative/reparative healing process consists of 3 overlapping phases: in-flammatory, proliferative with granulation, and remodeling with contraction.

� Appropriate presenting complaints are diverse and include occipital and suboc-cipital headaches; pain in the posterior midline and paramedial cervical spine, thecervicothoracic spine, the thoracic spine, the thoracolumbar spine, the lumbarspine, the lumbosacral spine, the scapula, and the shoulder regions; painbetween the shoulder blades, pain in the low back, buttocks, sacroiliac, trochan-teric areas; and any combination of the aforementioned complaints.

� Theextant literature, although it doesnotoffer convincingevidenceas to theoverallefficacy of prolotherapy, does offermoderate evidence to show its effectiveness inselect patients when used with appropriate technique and co-interventions.

BOTULINUM TOXIN (BTx) injection

Injectable BTx is frequently used in both physiatric and pain practices. In generalphysiatry, it is commonly used to treat spasticity, such as that found after a strokeor spinal cord injury. Within pain practices, it is used for a variety of pain syndromesand is often used off-label. The mechanism of action and other theoretic aspects ofthese toxins are discussed earlier in this article as is their use for TPIs (which is alsoconsidered off-label). BTx comes in a variety of formulations, including type A (Botox,Dysport, and Xeomin) and type B (Myobloc). Botox is Food and Drug Administration(FDA) approved for use in migraine headaches (as discussed elsewhere in this edition).For the remainder of the current article, the authors focus on the use of BTx for cervicaldystonia, thoracic outlet syndrome, and piriformis syndrome.

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In addition to having received FDA approval for migraine headaches, some forms ofBTx are FDA approved for use in cervical dystonia. Cervical dystonia, also known asspasmodic torticollis, is a cervical spine condition characterized by involuntary con-tractions of the neck and/or shoulder muscles resulting in abnormal head postures.Neck pain is often an associated symptom in cervical dystonia. BTx injections havebeen shown in multiple randomized controlled trials to effectively relieve the involun-tary contractions, spasms, and pain associated with this condition.50

Thoracic outlet syndrome (which may actually be a variant of cervical dystonia) isanother condition in which the use of BTx injections may be indicated. Thoracic outletsyndrome is a controversial diagnosis characterized by neurovascular compressionwithin the thoracic outlet. This condition often results from a combination of hyperton-ic/dystonic muscles, especially the anterior and middle scalenes. Injecting BTx intothese muscles has been shown to effectively relieve the symptoms of thoracic outletsyndrome.51 Although BTx is not FDA approved for the treatment of thoracic outletsyndrome, if the thoracic outlet syndrome is a secondary condition caused by cervicaldystonia, then one could make a case for the use of BTx as an FDA approved indica-tion in this scenario.Piriformis syndrome is another controversial diagnosis. It is characterized by sciatic

nerve irritation/compression from presumed hypertonicity of the piriformis muscle.Typical patients describe a deep pain in the buttock and can have symptoms thatmimic those associated with a classic L5 and/or S1 radiculopathy. Some cliniciansrefer to piriformis syndrome as pseudosciatica. In addition to piriformis syndrome be-ing a controversial diagnosis, the treatment is similarly controversial, especially withthe use of BTx. If priformis syndrome is indeed caused by piriformis hypertonicity,BTx would likely be effective in reducing the hypertonicity and taking pressure offthe sciatic nerve. This use is currently off-label, but several studies do demonstratethe effectiveness of BTx for this condition.52,53

Key Points

� BTx can be used for various pain diagnoses, including migraines, cervical dysto-nia, thoracic outlet syndrome, and piriformis syndrome.

� The use of BTx for pain procedures is often off-label, and its use is consideredcontroversial.

SUMMARY

Even in the setting of chronic pain, various injections can still have a useful role in facil-itating a rehabilitation program. Spinal injections, such as epidural steroid injectionsand facet joint injections, are among the most commonly used procedures inpain practices; however a growing number of practices are considering less commoninjections, such as various TPIs, regenerative injections/prolotherapy, and injectionsusing BTx.

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