Botulinum Toxin Therapy for Prevention of Postsurgical Pain

(1)

Botulinum Toxin Treatment Program, Yale School of Medicine, New Haven, CT, USA

Abstract

Postsurgical pain is a common disorder which results from spasm of muscles or sphincters and peripheral nerves after surgery. Persistent postsurgical pain results in application of polypharmacy and may lead to lengthy hospitalization.

This chapter reviews the data in intraoperative, intramuscular, or intra-sphincteric use of botulinum neurotoxins (BoNTs) for relief of postsurgical pain. As examples, five areas of postsurgical pain are chosen in which blinded or prospective, open-label studies are available. These consist of pain syndromes after mastectomy, hemorrhoidectomy, adductor release surgery in cerebral palsy, hernia repair, and cholecystectomy. The collective results of these reports are encouraging. They not only suggest the efficacy of botulinum neurotoxins (mainly onabotulinumtoxinA) for prevention of postsurgical pain but also suggest that treatment with BoNTs in these syndromes may have predictive value regarding the efficacy of certain surgical procedures which are currently employed to relieve such pains.

Keywords

PainMastectomyHemorrhoidectomyAdductor release surgeryHernia repairCholecystectomyBotulinum neurotoxinBotulinum toxinOnabotulinumtoxinAonaAAbobotulinumtoxinAaboA

Introduction

Following a number of surgical procedures, the muscles affected by surgery may contract and cause local muscle spasms and pain. In 20–40 % of the patients, pain can be severe, responds poorly to analgesic medications, and impairs the quality of life (Gerbershagen et al. 2013). A growing body of the literature strongly suggests that injection of BoNT into the involved muscles before the intended surgical procedure can reduce and sometimes prevent the postsurgical pain. Alleviation and prevention of postsurgical pain are obviously of significant importance to the patient.

Postmastectomy, Reconstruction, and Breast Expansion Pain

Following mastectomy, breast reconstruction, and expansion, many patients experience postoperative pain. It is now recognized that postmastectomy/breast expansion pain results mainly from the spasm of the pectoralis muscle. These painful spasms can occur acutely but, in some cases, continue for months and years after surgery. The pain has been attributed to muscle hypoxia, leading to muscle fiber degeneration and fibrosis (Gur et al. 1998). In some patients, spasms of pectoralis muscle may be quite severe and debilitating (Senior 2000; Wong 2000). In order to avoid such pain, continuous infusion of lidocaine through a catheter has been proposed and employed in a large number of patients (Pacik et al. 2003). Though effective, the procedure is cumbersome and carries the risk of infection. Persistent pain after reconstructive surgery may require special procedures such as bilateral pectoral neurectomies (Mast 1999; Hoffman and Elliot 1987).

Winocour et al. (2014) reviewed the literature in the use of botulinum toxins for prevention or treatment of postmastectomy pain. They cited a total of eight studies in which injection of the neurotoxin was used for pain prevention. Most studies were considered weak with a rating of <5 in Newcastle–Ottawa Scale (NCOS 0–8). Only the study of Layeeque et al. (2004) was given a rating of 7 (on NCOS scale), for having a good design despite being a non-blinded study. The utilized dose of the toxin was comparable between different studies (100 units for onaA), and the investigators found injection of BoNTs intraoperatively helpful in preventing postmastectomy pain.

Layeeque et al. (2004) conducted a prospective, randomized study in 48 patients who were undergoing mastectomy followed by placement of expander. Twenty-two patients received onabotulinumtoxinA (onaA), and 26 did not. The groups were comparable in terms of age, tumor size, and expander size. In the onaA group, 100 units of toxin was diluted with 40–60 cc of saline and injected at four sites into the pectoralis muscle before surgery (Fig. 13.1). Pain was evaluated through visual analog scale (0–10). The group that received onaA experienced less pain shortly after surgery and during expansion procedures (p < 0.0001 and p < 0.009). A number of other parameters also improved including shorter hospital stay and the dose of morphine required during hospital stay for pain control (Table 13.1). No side effects were reported.

Fig. 13.1

Technique of injection into pectoralis muscles (From Layeeque et al. (2004). With permission from Wolters Kluwer Health)

Table 13.1

Comparison of variables between BoNT group and Standard group

Characteristics	BT group, n = 22 (46 %)	Standard group, n = 26 (54 %)	p value
Immediate postoperative pain	3.09 ± 0.92	6.80 ± 1.98	<0.0001
Length of hospital stay, h	26 ± 8	37 ± 19	0.015
Dose of morphine used during first 24 h, mg	3.27 ± 3.18	17.15 ± 10.40	<0.0001
Pain during initial expansion	1.95 ± 1.88	5.61 ± 2.77	1.6 × 10⁻⁶
Pain during final expansion	1.04 ± 1.65	2.76 ± 1.99	0.009
Number of expansion sessions	5.72 ± 1.48	7.27 ± 3.07	0.0260
Time between mastectomy and permanent implant insertion, mo	6.57 ± 3.59	5.76 ± 2.54	0.448

From Layeeque et al. (2004)

Contrary to the above reports, a recent, double-blind, placebo-controlled study on 23 patients (class II) reported failure of BoNT to prevent this kind of pain (Lo and Aycock 2013), however. All patients had bilateral mastectomy. Investigators injected 100 units of BoNT in 1 side and saline in the other side into the pectoralis muscles. No difference between the pain scores was found between the toxin group and the placebo group.

Comment

A number of small, open retrospective studies and one well-designed prospective study which included a control group strongly suggest the efficacy of BoNTs in preventing postmastectomy/expander placement pain. The results of a recently published blinded study, however, stand at odds with the encouraging data presented from open-label trials. The reason for this discrepancy is not clear. The difference between techniques and small size of the recent blinded study may be a contributing factor. Larger, controlled studies are needed to define the role of intraoperative pectoralis muscle injection with BoNTs in prevention of pain that develops postmastectomy, insertion of expanders, and reconstructive procedures.

Post-hemorrhoidectomy Pain

Hemorrhoid is one of the most common forms of human ailments with a prevalence of 4–36 % (Altomare and Giannini 2013). Men and women are equally affected. The prevalence increases with age from the beginning of adulthood until the seventh decade and declines thereafter. More individuals are affected in the higher socioeconomic groups and among the Caucasians and Jews (Loder et al. 1994). Hemorrhoidectomy ranks among the most common procedures in the USA and Europe with an annual rate of 60 and 46 per 100,000 of individuals reported in the USA and France, respectively (Johanson and Sonnenberg 1991; Tiret et al. 1988).

Postsurgical pain after hemorrhoidectomy is common and can be severe and exhausting. The pain can occur at rest or during defecation and is generally attributed to spasm of the internal anal sphincter.

Treatment of Post-hemorrhoidectomy Pain

The first line of treatment is proper diet and pharmacological therapy which includes the use of acetaminophen, nonsteroidal anti-inflammatory analgesic drugs, muscle relaxants, and opioids. In recent years, blinded and placebo-controlled studies have shown partial efficacy of two forms of topical ointments. Glyceryl trinitrate ointment (0.2 %) is now commonly used for treatment of post-hemorrhoidectomy pain based on controlled investigations (Elton et al. 2001; Hwang et al. 2003; Tan et al. 2006). In one study (Khan et al. 2014), a combination of glyceryl trinitrate ointment with lignocaine (lidocaine 2 % and GTN 0.2 %) has been found better than either treatment alone. Calcium channel blocker (CCB) ointments also have shown efficacy against post-hemorrhoidectomy pain in two blinded placebo-controlled studies (Amoli et al. 2011; Perrotti et al. 2010). In both studies (one using diltiazem and the other nifedipine), the pain was considerably less at 7 days postsurgery in patients taking CCB compared to the placebo group (p < 0.05).

In case of persistent pain, other measures may be employed which have shown some efficacy in blinded studies. These consist of local anesthetic infiltration (Ho et al. 2000), anesthetic regional blockage (Luck and Hewett 2000), transdermal fentanyl (Kilbride et al. 1994), and diathermy excision (Andrews et al. 1993). More details on various approaches to manage post-hemorrhoidectomy pain can be found in a recent review by Siddiqui et al. (2011).

Botulinum Toxin Treatment of Post-hemorrhoidectomy Pain

The controlled studies on this subject include three blinded studies with a placebo arm and one randomized, prospective comparator study.

Blinded, Placebo-Controlled Studies

Davies et al. (2003) conducted a double-blind, placebo-controlled study in 50 consecutive patients who were undergoing Milligan–Morgan hemorrhoidectomy. OnabotulinumtoxinA or saline was injected at two points (0.2 cc site) into the posterior midline of the internal anal sphincter via a 27 gauge needle. In case of onaA, the preparation was 50 units in 1 cc of saline; hence, 0.4 cc of the solution contained 20 units of the toxin. At the end of the procedure, both groups were injected with 20 ml of bupivacaine (0.25 %) into the perianal skin. Patients were also prescribed a 7-day supply of co-codamol 30/500 (codeine phosphate 30 mg, paracetamol 500 mg, four times per day orally) and instructed to use this as required. Pain was assessed by visual analog scale (0–10) at baseline and then daily via a questionnaire for the 7 days following the procedure. The mean pain score at postoperative days 6 and 7 was significantly less in the patients who had onaA injections (p < 0.05). No side effects were reported.

In another blinded and placebo-controlled study of 30 patients, the effect of BoNT-A versus saline was investigated in peri- and post-hemorrhoidectomy symptoms including pain (Patti et al. 2005). Patients had grades III and IV hemorrhoids. In the toxin group, the solution was prepared by adding 2 cc saline to the onaA vial of 100 units (50 units/cc). Then 0.4 cc (20 units) was injected into the anterior midline of the anal sphincter at two points. The control group received the same volume of saline. Patients were assessed at baseline and followed for 30 days.

The postoperative pain measured by VAS was significantly less in the onaA group compared to the placebo during the first 7 days (p = 0.001). Subsequently, patients in the placebo group used a larger number of analgesic tablets compared to the onaA (22.3 ± 5.1 vs. 14.8 ± 6.2; p < 0.05). In the placebo group, the manometric anorectal resting pressure (MRP) was significantly raised (p < 0.05) on the fifth postoperative day, whereas it was significantly reduced (p < 0.01) in the onaA group. The length of wound healing was 23.8 ± 4.1 days in the onaA group compared to 31.3 ± 5.5 days in the placebo group (p < 0.05). The same investigators (Patti et al. 2008) found very similar positive findings in another double-blind study which assessed efficacy of intra-sphincter injection of onaA in relieving the pain of inoperable, thrombosed hemorrhoids. The type of toxin, dose, and technique of injection were identical to their postsurgical study.

In contrast to the two abovementioned studies in post-hemorrhoidectomy pain, a third placebo-controlled study of 32 patients with grades III and IV hemorrhoids found no improvement of postoperative pain and no change in RMP after injection of BoNT-A into the intersphincteric space (Singh et al. 2009). The BoNT group, however, demonstrated significantly lower squeeze resting pressure (p < 0.05) compared to the placebo. The authors used 150 units of abobotulinumtoxinA diluted in 0.5 cc of saline in this study. Pain and MRP were assessed over 14 days (13 and 13 patients in each group).

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