Interventional therapy and injected agents for orofacial pain and spasm (including botulinum toxin)
11.1 Needle- and Injection-Based Interventional Treatments
A variety of needle-based and injection-based interventional therapies exist for chronic pain and this chapter examines the evidence for these therapies. The chapter is divided into two main parts. The first part discusses various needle- and injection-based therapies (e.g., acupuncture, local anesthetic, cryotherapy, phenol, glycerol, and dextrose solutions) that are used for orofacial pain. Corticosteroid injections are discussed in the chapter on arthritis pain (Chapter 18). The second part of this chapter discusses botulinum toxin (BoNT [i.e., botulinum neurotoxin]) injections, including some background on BoNT as a medicinal therapy, and how it is used in both spasm control and pain control.
Acupuncture encompasses a range of procedures, including manual needling, electrical acupuncture, moxibustion, acupressure, heat, and laser stimulation of acupuncture points. Using a Chinese medical philosophy that disease occurs when there is a disruption of normal energy flow called Qi, over 2000 acupuncture points arranged on “meridians” have been mapped representing channels of energy flow. The stimulation of these points corrects the imbalances of Qi. While the history of acupuncture is quite ancient, modern science has only evaluated its efficacy within the past two decades. In 1990 a meta-analysis evaluated the efficacy of acupuncture as a treatment of chronic pain. The authors concluded that acupuncture as a therapy for chronic pain is, at best, doubtful.1 In 1997 a National Institutes of Health (NIH) consensus conference examined the literature and offered a statement on the current evidence for using acupuncture.2 This prestigious body concluded that “Although there have been many studies of its potential usefulness, many of these studies provide equivocal results because of design, sample size, and other factors.” It also concluded that acupuncture analgesia has been demonstrated in controlled laboratory studies to produce greater analgesia than appropriate placebos.3 The mechanism of acupuncture has been hypothesized as counterirritation analgesia and is essentially a brainstem mechanism in which a brief, intense stimulation of afferent nerve fibers induces a brainstem inhibitory control structure to modulate pain response. This response activates both opioid and nonopioid systems. Unfortunately, the NIH conference did not comment on the efficacy of acupuncture for treating chronic pain disorders.4
In 1999 and 2000, there were three systematic reviews of the literature published that assessed the efficacy of acupuncture (primarily manual needling) on chronic pain. Each review dealt with a different disease group (fibromyalgia, chronic pain of all types, and low back pain) and each reached a different conclusion. The first review focused on fibromyalgia but it was not a Cochrane Library–based review.5 It concluded that acupuncture was better than sham-acupuncture. The second review focused on acupuncture for chronic pain (of all types) and was also not Cochrane Library based.6 It concluded that the available studies were not of sufficient methodological quality to offer an endorsement. The third review focused on acupuncture for management of acute and chronic low back pain and it was a Cochrane Library review.7 It examined 11 clinical trials but stated that only two were of sufficiently high quality. It also concluded that current evidence was not of sufficient methodological quality to offer an endorsement.
With regard to orofacial pain, in 2007 an article described the short-term effect of acupuncture on myofascial pain patients after clenching.8 Visual analog scales (VAS) were used to rate the pain in 15 chronic myofascial pain patients using a single-blind, randomized, controlled, clinical trial with an independent observer. Subjects were randomly assigned into two groups (acupuncture [n = 9] and sham-acupuncture [n = 6]). Acupuncture or sham-acupuncture was administered at the Hegu Large Intestine 4 acupoint and facial–jaw pain was then induced or exacerbated by having subjects clench their teeth continuously for 2 minutes. An algometer invoked a mechanical pain stimulus to the jaw muscles, and the subject rated his or her pain level using a VAS. Pain tolerance in the masticatory muscles increased significantly more with acupuncture than sham-acupuncture. An additional study in 2007 examined the effect of acupuncture-like electrical stimulation on chronic tension-type headache using a randomized, double-blinded, placebo-controlled trial in 38 chronic tension-type headache patients.9 These patients were randomized into a treatment group and a placebo group. Pain duration and pain intensity were recorded on a 0–10 cm VAS, and the number of headache attacks and use of medication were recorded in a 2-week diary. The treatment was a surface electrode attached to an electrical stimulator or a sham stimulator and they were instructed to use the device at home. Six acupoints were used in the treatment (bilateral EX-HN5, GB 20, LI 4) and treatment was to be applied for 3 minutes twice a day. Data was collected 2 weeks before treatment, at 2- and 4-week points during treatment, and at 2, 4, and 6 weeks after treatment. Although both pain duration and pain intensity decreased during treatment there were no significant group differences. The only group difference was for a decrease in analgesic use in the acupuncture group, but not in the sham-acupuncture group.
To summarize, no definitive conclusions about acupuncture for chronic orofacial pain can be made. The lack of quality data combined with recent studies of better quality has only suggested short-term and minimal effects from acupuncture overall. Until additional scientifically valid studies are published, acupuncture as a treatment for chronic orofacial pain may provide, at best, transient pain relief. However, this may be an acceptable clinical strategy for some chronic pain sufferers and the treatment is generally a low-risk procedure.
11.1.B Trigger-Point Injections
Injection of a local anesthetic is a common treatment for myofascial trigger points; more recently BoNT has been used, which is discussed later in this chapter. The local anesthetic may allow better stretching of the taut band in which the trigger point resides, and it may desensitize the trigger point.10 Trigger-point pathogenesis is covered in the chapter on myogenous disease (see Chapter 16). Unfortunately, not a great deal of high quality evidence exists on the efficacy of trigger-point injections versus a control (sham injections) or comparison therapy (e.g., acupuncture) for myofascial pain.
In 1981 a controlled randomized double-blind crossover clinical trial examined the injection of bupivacaine 0.5%, etidocaine 1%, or saline into trigger points in 15 patients with myofascial pain.11 Outcome measures were based on the patient’s subjective pain response to these injections 15 minutes, 24 hours, and 7 days after treatment. The authors concluded that trigger-point injections with bupivacaine and etidocaine were generally preferred over saline. In 1989 a prospective randomized, double-blind study evaluated 63 subjects with low back pain treated with one of four treatments (0.5% lidocaine, 0.5% lidocaine combined with a steroid, acupuncture, and vapocoolant spray with acupressure).12 No significant difference was found between the different methods of treatment, and the authors concluded that injection of lidocaine is not the critical factor, since direct mechanical stimulus to the trigger point seems to give an equal effect.
In 2001 a review article examining the previous studies and others concluded that trigger-point injections using anesthetic solutions were no better than injecting sterile saline or dry needling alone.13 However, this finding does not mean that trigger points are placebo therapy and it might be better to conceptualize them as acupuncture-like therapy, namely, a treatment that induces a temporary pain suppression effect at best. This point of view is supported by a 1988 study that investigated the use of intravenous naloxone (an opioid receptor antagonist) given after trigger-point injection therapy.14 The double-blind, crossover study included 10 patients with myofascial trigger point pain; each patient received an injection of 0.25% bupivacaine, which generally decreased their pain and increased range of motion. Following these injections, patients received either an intravenous infusion of naloxone (10 mg) or saline in a crossover design. All improvements afforded by the trigger-point injection therapy were significantly reversed with intravenous naloxone but not so with intravenous placebo. These results point to an endogenous opioid system as a mediator for the decreased pain and improved physical findings following the anesthetic injections.
More recently several additional experimental studies on trigger points and one new meta-analysis have been published. In 2005 a single-blind study compared 0.5% lidocaine injection, 10–20 units of botulinum toxin type A (BoNT/A [also BoNT-A]), and dry needling of trigger points in 29 patients (23 females; 6 males) with myofascial pain using 87 individual trigger points in the cervical and/or periscapular regions.15 Subjects were randomly assigned to one of the three treatment methods and cervical range of motion, trigger-point pain pressure threshold (PPT), pain scores (PS), and VAS for pain, fatigue, and work disability were evaluated at entry and after 4 weeks. All treatments were followed by daily self-stretching of the muscle groups involved. The authors reported that PPT and PS significantly improved in all three groups but in the lidocaine-treated group, PPT values were significantly higher than in the dry needle group. Pain scores were also significantly lower for the lidocaine-treated group than in both the BoNT/A and dry needle groups. Finally, VAS pain scores significantly decreased in the both the lidocaine-treated group and BoNT/A-treated groups but not in the dry needle group. The authors concluded that lidocaine injections were more practical and rapid, and less expensive than BoNT/A treatment and both were better than dry needling. In 2007 a study reported on the efficacy of intramuscular and nerve root stimulation versus 0.5% lidocaine injection to trapezius muscle trigger points in 43 myofascial pain patients.16 The subjects were divided into two groups and treatment was rendered on days 0, 7, and 14. The results shows that intramuscular stimulation was more effective than trigger points, using pain scale scores at all visits. Another 2007 study compared acupuncture needling versus 0.5% lidocaine injection in upper trapezius muscle trigger points in 39 elderly myofascial pain patients.17 The subjects were divided into two groups and all received treatment at 0, 7, and 14 days and outcomes were assessed at 28 days. Both groups improved, but there was no significant difference in reduction of pain between the two groups. In 2008, the effectiveness of injection therapy (e.g., corticosteroids or anesthetics) for low back pain was examined in a recent meta-analysis. The patients on which these injections were used all had subacute or chronic low back pain.18 The study examined papers between 1999 and 2007 in multiple languages. They included only RCTs on the effects of injection therapy involving epidural, facet, or local sites for subacute or chronic low-back pain. The authors concluded that there was no strong evidence for or against the use of any type of injection therapy.
In summary, the preponderance of data suggests that trigger-point injections using low amounts of anesthetic solutions were no better than injecting sterile saline or dry needling of the trigger point. This would suggest that this form of therapy is best conceptualized as an acupuncture-like therapy, namely, a treatment that induces a short-lived pain-suppression effect.
The injection of various solutions aimed at producing a sclerosing effect has been used to treat soft-tissue injuries (e.g., inguinal hernia) for more than 100 years. In the 1930s, this treatment approach was applied to injured joints in an attempt to stimulate connective tissue repair. Although several studies have been published about this method of treatment for various orthopedic and spinal indications (termed prolotherapy), its use remains controversial. In both 200419 and 200520 critical reviews of the literature examined intraligamentous injection of sclerosing solutions (i.e., prolotherapy) for spinal pain. The 2004 report found four randomized or quasi-randomized clinical trails and the 2005 report found five trials that were randomized clinical trials (RCTs). Neither review was able to make definite conclusions about the efficacy of prolotherapy versus control injections. It was pointed out in the 2005 review that in general these studies did not use a consistent sclerosing agent and in fact 20 different sclerosing solutions were used. The most common sclerosing agent used was a mixture of dextrose 12.5%, glycerin 12.5%, phenol 1.25%, and lidocaine 0.25%. Looking at the individual studies, two showed significant differences between the treatment and control groups but in one co-interventions confounded interpretation of results and in the other the data analysis revealed no significant difference in mean pain and disability scores between the groups. A third and fourth study found little or no difference between groups in pain and disability. The most updated review (in 2008) described two randomized controlled trials in which prolotherapy was administered using 6 weekly injections of 20–30 mL of a combination solution containing dextrose, glycerin, phenol, and lidocaine.21 Injections were given in conjunction with spinal manipulation therapy and exercise and both demonstrated positive results. No evidence for efficacy of prolotherapy injections alone was concluded.
Most of the available studies focus on back pain and other regions of the body and no convincing data shows prolotherapy to be effective in the absence of co-interventions such as spinal manipulation therapy. The use of a sclerosing solution for pain in the head and neck has never been evaluated with a randomized blinded controlled clinical trial; therefore, currently no acceptable evidence of efficacy for prolotherapy injections for the treatment of trigeminal-nerve-related pain exists.
11.1.D Occipital Nerve Block for Headache
Occipital nerve blockade (ONB) is a diagnostic and treatment procedure where anesthetics (typically lidocaine or bupivacaine, sometimes with a corticosteroid agent added) are injected near the occipital nerve on the back of the head near the base of the skull. In 2006 a retrospective chart review study assessed the outcome of patients who had frequent primary (migraine and cluster) headaches who had received occipital nerve blockade containing local anesthetic and corticosteroid agents.22 The authors reported that 26 of 57 (46%) ONB injections in 54 migraineurs yielded a complete or partial pain reduction response that lasted a median of 30 days. For cluster headache 13 of 22 ONB injections yielded a complete or partial pain reduction response lasting a median of 21 days. The authors speculated that tenderness over the greater occipital nerve was strongly predictive of outcome but, of course, scientific evidence is not based on retrospective chart reviews.
A 2006 double-blind randomized controlled study examined the effect of occipital nerve blockade on cervicogenic headache.23 Analgesic consumption was the primary outcome of the study. Fifty adult patients diagnosed with cervicogenic headache were randomly divided into either receiving preservative-free normal saline or local anesthetic. The authors reported that analgesic consumption, duration and frequency of headache, nausea, vomiting, photophobia, phonophobia, decreased appetite, and limitations in functional activities were significantly less in the block group compared with the control group at the 2-week follow-up point. Finally, in 2007 a single patient case described the beneficial effect that massaging over the greater occipital nerve has on migraine headaches.24 The authors speculated that this was evidence of trigemino-cervical convergence and massage produced a diffuse nociceptive inhibitory control (DNIC) that was inhibitory to the migraine mechanisms.
In summary, a randomized controlled study reported that occipital nerve blockade with lidocaine was more effective in pain reduction in cervicogenic headache sufferers than a placebo injection at the 2-week follow-up point.
11.1.E Sphenopalatal Nerve Block
The sphenopalatine ganglion is located in the sphenopalatine (pterygopalatine) fossa, posterior to the middle turbinate and inferior to the maxillary nerve. Anesthetic blockade of this ganglion has been reported to be effective in the relief of a wide variety of facial pains and headaches. It can be anesthetized either via the transnasal approach, using cotton applicators soaked with 4% lidocaine inserted into the nose passing along the upper border of the inferior turbinate and directed backward until the upper posterior wall of the nasopharynx, or via the intraoral approach with injection of local anesthetic through the greater palatine foramen. Unfortunately there is little or no randomized controlled clinical trial data on this method in spite of the fact that sphenopalatine ganglion blocks have been used to treat headache and facial pain for many years.
In 1998, a study examined the use of sphenopalatine ganglion blockade (SPGB) for the treatment of chronic myofascial pain of the head, neck, and shoulders.25 This study was a double-blind, placebo-controlled, triple crossover study involving 23 myofascial pain patients that compared SPGB with either 4% lidocaine or saline. In a washout period between these two treatment conditions, all patients received trigger-point injections (TPIs) using 1% lidocaine. Treatment order was randomly assigned and they consisted of either (1) SPGB with 4% lidocaine, then TPI with 1% lidocaine, and SPGB with saline or (2) SPGB with saline, then TPI with 1% lidocaine, and SPGB with 4% lidocaine. Treatments were given sequentially at 1-week intervals for both groups. Pain scores using VAS were gathered before, 30 minutes, 6 hours, 24 hours, and 1 week after each treatment. The authors reported that the analgesic effect of SPGB with 4% lidocaine was no better than placebo and actually less efficacious than administration of standard TPIs for the treatment of myofascial pain of the head, neck, and shoulders.
Sphenopalatine ganglion blockade is used for atypical facial pain and cluster headache more commonly than myofascial pain, so the above study did not dissuade practioners from using this treatment in these conditions. In fact in 2006 a report appeared in the literature which described a transnasal sphenopalatine ganglion injection.26 The transnasal application of topical anesthetic is the simplest and most common technique but also more variable in its effect. Another described the effect of blocking the sphenopalatine ganglion.27
In summary, at this point there have been no controlled studies that have examined the effect of sphenopalatine ganglion block for chronic neurovascular or neurogenic pain in the trigeminal nerve region, including atypical facial pain or cluster headache. For myogenous pain in the head and neck region, sphenopalatine ganglion block with lidocaine was examined in a randomized controlled trial and was found no better than the effect induced with a saline injection.
11.1.F Stellate Block
A sympathetic nerve block is one that is performed to determine if the pain can be related to spontaneous activity of the sympathetic nerves. The supply of sympathetic fibers to the head is through the stellate ganglion. Normally the injection involves infusion of lidocaine but the injection of opioid drugs close to the sympathetic ganglia has been reported to provide good pain relief without side effects in patients with postherpetic neuralgia, sympathetically maintained pain, and reflex sympathetic dystrophy.28–30 In 2006 an article described three patients with medication-resistant chronic headache or idiopathic facial pain who were treated with an injectable opioid (buprenorphine) applied to the region at the stellate ganglion.31 The authors reported a decrease in pain intensity, reduction of pain medications, and improvement in quality of life as a result of these injections. In contrast to this report Spacek et al. showed no benefit of buprenorphine, compared with placebo.32 These authors conducted a randomized, controlled, double-blind, crossover study on stellate ganglion opioid injections in refractory trigeminal neuralgia. In the two groups, either buprenorphine or 0.9% sodium chloride (saline) was applied to the superior cervical ganglion; significant pain relief occured in both groups. Another study describes a series of opioid injections applied in the area of the superior cervical sympathetic ganglion on patients with atypical orofacial pain, burning mouth syndrome, and glossodynia.33 The authors of this paper suggested that a very large placebo effect explains the temporary improvement of symptoms. In 2008 another randomized comparison study examined the role of stellate ganglion block (SGB) for facial pain.34 It enrolled 50 patients with chronic facial pain of various origins (traumas, iatrogenic issues, herpes zoster, or neurological pathologies). The study provided (1) SGBs using 10 administrations of 10 mg of levobupivacaine given every other day, followed by one administration per month for 6 months thereafter or (2) tramadol 100 mg/day and gabapentin 1800 mg/day orally for 6 months. The results reported were that the mean VAS pain level reported by patients was greatly reduced (8.89 down to 0.2) and it remained at that reduced level for the 6th and 12th months. For the tramadol group the VAS pain score was also reduced (from 8.83 to 4.9 after 12 months). Of course an injection therapy versus a prescription drug does not remove the therapeutic bias and strong placebo response induced by the injection of an anesthetic into the neck multiple times. Furthermore, this population was a quite mixed diagnostic group, so the chronicity of diseases being treated is also suspect.
In summary, it appears that the predominate pain reduction effect in a group of refractory trigeminal neuralgia pain patients produced by an injection of opioid agent or a local anesthetic agent into the area of the superior cervical sympathic ganglia is probably a powerful placebo response. Until additional studies are done examining this effect in more detail, stellate ganglion blocks are proven effective through double-blind random controlled trials.
11.1.G Intra-Articular Morphine and Other Substances
In 2001 a randomized double-blind parallel group multicenter study evaluated the use of a single dose of intra-articular morphine on 53 patients with unilateral temporomandibular arthralgia or osteoarthritis.35 VAS pain scores at maximum mouth opening and at jaw rest were collected in a diary 3 days before and 5 days after intra-articular injection of either 1.0 mg morphine HCl, 0.1 mg morphine HCl, or saline (placebo) into the temporomandibular (TMJ). The authors reported that the VAS pain score at maximum mouth opening was considerably reduced for up to 10 hours after injection but without significant differences between groups. Interestingly at the follow-up, the median VAS pain score at maximal mouth opening was significantly lower in the 0.1-mg morphine group than in the 1.0-mg morphine or in the saline group. There was no difference in the incidence of adverse events between the groups and overall they were few in number. The authors concluded that the evidence for the analgesic property of the locally applied opioid was inconclusive.
Confirming this study a randomized double-blind controlled clinical trial which examined pain relief from intra-articular saline with or without morphine 2 mg in patients with moderate-to-severe pain after knee arthroscopy.36 In this study the pain intensity decreased from about 50 to about 10–15/100 in both groups and the sum of pain intensity differences at 2 and 22 hours was not significantly different between the two groups. Considering the data from both of the above studies it would suggest that opioid receptors inside joints are few in number and even arthritic pain does not readily induce upregulation of these receptors. One interesting more recent animal experiment has actually shown that if more opioid receptors were present inside arthritic joints, this might be a way of reducing arthritic pain and destruction.37 This experiment induced human μ-opioid receptor (HuMOR) expression in arthritic joints of mice using a DNA-containing viral vector into the temporomandibular joints of transgenic mice. The results of this paper showed that MOR overexpression in joints successfully prevented pain and dysfunction in these animals.
In summary, quality research shows that the analgesic property of the locally applied opioid to the temporomandibular joint for arthralgia and osteoarthritis pain relief for the knee is not better than a placebo injection.
11.1.H Phenol Nerve Block for Trigeminal Neuralgia
Over the last 50 years, peripheral neuroablation of trigeminal nerve branches using a variety of substances has been described. In 1999, a retrospective chart review on 18 patients (9 females and 9 males) with diagnosed trigeminal neuralgia treated with trigeminal nerve peripheral branch phenol/glycerol injections for trigeminal neuralgia was published.38 Sixty injections of 10% phenol in glycerol were administered to 18 patients, 46 were administered into the infraorbital nerve canal, 11 were into the mandibular nerve just proximal to the mandibular canal, and 3 were into the supraorbital nerves canal. The reported results were that 87% of the injections produced marked or total relief initially and 37% of these still provided relief after 1 year and 30% after 2 years. There were no serious complications or dysesthetic pain reported in these 18 patients; although most had full facial sensory loss postinjection, this generally recovered within 6 months and was well tolerated.
In 1998 a prospective case study on nine patients described the effect of peripheral absolute glycerol neurolysis inducing injections on trigeminal neuropathic pain after nerve injury.39 Although this is an uncontrolled study, the interesting aspect of the report is that the authors performed a quantitative sensory testing before and after the injections to document changes in abnormal pain and sensory perception in these nine patients. The injections of glycerol were performed proximal to the site of nerve injury. The authors reported little or no effect on pain levels in eight patients at 6 weeks after injection, although in one patient complete and sustained pain relief was observed. The authors speculated that pain relief in the one patient was probably related glycerol’s ability to inhibit ongoing ectopic activity in the damaged nerve.
To summarize this section, uncontrolled studies and case reports are not proof of efficacy and these descriptive reports need to be followed with reasonable quality scientific studies. Finally, a 2002 review of the literature examined how ganglion-based neuroablation compared with peripheral neuroablation in trigeminal neuralgia patients.40 The authors reviewed available literature and concluded that expertly performed ganglion-level procedures (radiofrequency thermocoagulation, balloon compression, and glycerolysis) were more effective than peripheral procedures but neither approach was likely to produce long-term pain relief.
Several case reports in the literature report efficacy of cryoneuroablation of peripheral nerve branchs as an effective method of treating atypical facial pain and even trigeminal neuralgia.41–43 In 1988 a retrospective review of 145 patients with paroxysmal trigeminal neuralgia claimed pain relief lasted from 13 to 20 months in different branches of the trigeminal nerve.44 This report stated that patients regained normal sensation long before the return of pain and did not claim any major adverse events. In a 2002 case series 19 patients with trigeminal neuralgia had either the infraorbital nerve or the inferior alveolar nerve frozen using a cryoprobe.45 This report claimed that the pain was absent for at least 6 months but did recur in 13 out of 19 patients within 6–12 months.
In summary, there are several claims in the literature that cryoneuroablation can relieve peripheral nerve branch pain, and that it might be effective for treating atypical facial pain and even trigeminal neuralgia; however, to date there have been no controlled randomized blinded studies using cryoneuroablation applied to peripheral branches of the trigeminal nerve for the management of chronic facial pain of any type.
11.1.J Recommendations on Interventional Therapy for Chronic Orofacial Pain
At present no Cochrane study is available that examined needle- and/or injection-based therapies for the treatment of chronic orofacial pain. However, a Cochrane-style review cited earlier (Staal et al., 2009) examined the role of injection therapy for subacute and chronic low back pain. This study systematically reviewed randomized controlled trials (RCTs) that sought to determine if injection therapy is more effective than placebo or other treatments for patients with subacute or chronic low back pain. The authors discovered 18 eligible clinical trials (1179 participants) in their review. The injection sites varied from epidural sites and facet joints (i.e., intra-articular injections, periarticular injections, and nerve blocks) to local sites (i.e., tender and trigger points). Overall, the results indicated that there is no strong evidence for or against the use of any type of injection therapy for back pain. The general conclusions that can be derived regarding various forms of chronic orofacial pain from the specific therapy studies cited in Sections 11.1.A–11.1.I are listed at the end of the chapter (Sec. 11.3).
11.2 Botulinum Toxin in Orofacial Pain Disorders
The second part of this chapter reviews how BoNT evolved for medical purposes. The evidence is based on a critical review of the literature regarding the use of BoNT for both spasm and pain in the orofacial region.
11.2.A Botulinum Toxin As a Medicine
The concept that a toxin produced by the bacteria Clostridium botulinum might have medical uses came to mind in the 1920s after the botulinum neurotoxin (BoNT) was purified.46 This toxin was discovered to have several subtypes, which were serologically distinct (BoNT/A, B, C, D, E, F, and G).47
Botulinum Toxin Used “On-Label”
The US Food and Drug Administration (FDA) approved boulinum toxin type A (BoNT/A [Botox®, manufactured by Allergan, Irvine, CA]) in 1989 for focal muscle hyperactivity disorders (e.g., focal dystonias).48 Specifically, the FDA approved BoNT/A for the temporary treatment of blepharospasm and strabismus and then for cervical dystonia in 1990.49 In 2000, the FDA also approved Myobloc® (BoNT/B manufactured by Solstice Neurosciences, Inc., San Diego, CA) for the treatment of cervical dystonia in patients who developed BoNT/A resistance. Since then BoNT/A has been approved for the treatment of primary axillary hyperhidrosis (excessive sweating) and for reduction of deep glabellar lines in the face. BoNT/A is supplied in vials in a lyophillized form, at a dose of 100 units (U) per vial. Dysport® is marketed outside of the United States by Ipsen Ltd in Europe. All these preparations, Botox, Myobloc, and Dysport, differ in formulation and potency; hence, their units are not interchangeable.
”Off-Label” Botulinum Toxin Use
In addition to these on-label uses, BoNT/A is used off-label in the orofacial region to help treat primary and secondary masticatory and facial muscle spasm, severe bruxism, facial tics, orofacial dyskinesias, dystonias, and even idiopathic hypertrophy of the masticatory muscles. With the exception of hypertrophy, the common link for these conditions is that they are all involuntary motor hyperactivity disorders and, although they are off-label uses, they are similar in pathophysiology to the condition for which BoNT is FDA approved. Even more off-label is the suggested use of BoNT for pain disorders without clear-cut motor hyperactivity being present. These pain disorders include conditions such as chronic migraine headache, chronic daily headache, chronic myofascial pain, focal sustained neuropathic pain, and more recently episodic trigeminal neuralgia. Using a drug off-label sometimes generates interest from the medical, legal, and federal regulatory communities but off-label drug use is legal, and the FDA recognizes this. The practitioner’s professional judgment determines the best treatment possible for their patients, which may include off-label use of a medication. The practitioner who elects to use a drug off-label bears some inherent risk, and legal rulings have suggested that off-label drug use may be evidence of negligence. The practitioner should weigh potential benefit against the risk for the patient, and full disclosure of risk should be explained to the patient, including a consent form signed by both parties. The practitioner should have reasonable knowledge of the body of scientific evidence supporting the off-label application of a drug.
Mechanism of Action
Exocytosis of acetylcholine (ACh) on cholinergic-containing nerve endings of motor nerves is inhibited by BoNT/A.50 Autonomic nerves are also affected by the inhibition of ACh release at the neural junction in glands and smooth muscle.51 BoNT achieves this effect by its endopeptidase activity against SNARE proteins, which are a 25-kDa synaptosomal-associated protein required for the docking of the ACh vesicle to the presynaptic membrane. It has been suggested that when BoNT is used for the treatment of neuromuscular disorders, particularly focal dystonias and spastic conditions, patients have reported a marked analgesic benefit.52 This benefit was initially believed to be due to the direct muscle relaxation effect of BoNT. However, various observations have suggested that BoNT may exert an independent action on peripheral nociceptors by blocking exocytosis of such neurotransmitters as substance P (SP), glutamate, and calcitonin gene related peptide (CGRP). In addition, because BoNT does not cross the blood–brain barrier, and since it is inactivated during its retrograde axonal transport, the effect is believed to be in the first-order sensory nerve and not more centrally.53
Injection Preparation, Dosing, and Effect Duration
The BoNT/A is kept frozen (2–4°C) in a vial until it is ready to use. The drug is put into solution, following manufacturer’s guidelines, by adding normal saline (preservative-free 0.9% saline solution). Once prepared it should be used within 4 hours. The preferred syringe is a calibrated 1.0-mL tuberculin syringe, and the needle selected for injection is usually between 26 and 30 gauge. Skin preparation involves alcohol wipes and dry sterile gauze sponges. Aspiration before injection is recommended. Dosing is usually established by the diagnosis and reason for use of the toxin, size of the muscle, and medical conditions or medications. Until studies narrow down all specifics, the final dilution and dosage used is left to the clinical experience and discretion of the practitioner. The number of injection sites is usually determined by the size of the muscle. Theoretically, it may be appropriate to inject more sites with smaller doses, and using more injection sites should facilitate a wider distribution of BoNT/A to nerve terminals. However, too many injection sites may cause local injection site pain. The proper targeting of muscles is a crucial factor in achieving efficacy and reducing adverse effects from BoNT/A injections. The therapeutic effects of BoNT/A first appear in 1–3 days, peak in 1–4 weeks and decline after 3–4 months. Motor nerve block induced by BoNT/A has a duration ranging from 8 to 16 weeks.
Adverse Events and Side Effects
Side effects can be divided into (1) site-of-injection side effects and (2) medication-related side effects. With regard to site-of-injection side effects, the needles being used for most injections are small (between 27 and 30 gauge) and if the skin is cleaned properly, then the chances of local hematoma, infection, or persistent pain in the injection site are extremely low. Medication-related side effects are generally few, transitory, and well tolerated />