New Techniques: Antidote or Anecdote? The Tale of the Traveling Salesman
Anorectal Surgery. Often, a painful cure. And worse, the performance of the curative operation is only fifty percent of the battle. Sleepless nights await both the patient and the surgeon once the cure has been inflicted. Postoperative pain relief represents the other fifty percent of the battle.
Here is a short video of Dr. Hoffman speaking about Exparel and postoperative pain relief:
Thirty five million ambulatory surgical procedures are performed annually in the United States (1). Effective control pain control is essential for recovery, improved wound healing and reduced hospital admission rates. In evaluating hospital admission data of 20,817 patients undergoing same day surgery, 1.5% of them returned to the hospital in the postoperative period (2). Pain was the most common reason. There has been little progress in addressing this challenge.
Can We Do Better?
Surveys from 1993, 2003 and 2012 have demonstrated that postsurgical pain is common and that a similar distribution of the quality of perceived pain has remained unchanged (3-5). Patient pain scores are now being used as metrics in measuring the adequacy of care. Surveys from the Hospital Consumer Assessment of Healthcare Providers and Systems during 2008-2009, confirmed the need for improving postoperative pain management. Mean pain management scores were 68 of 100 in 3,765 participating hospitals. Data of this type may be used by the government and other third party payers in determining reimbursement rates. Surgeons and hospitals alike are being pushed to demonstrate improvement.
Several areas of improvement have helped in reducing postsurgical pain. A first line of defense against postoperative pain involves managing patient expectations. Patient education goes far in this regard. Preoperatively, patients are advised that their postoperative discomfort may occur along a spectrum of intensity and that their pain intensity and frequency may change constantly until healing is final. Allowing patients to “prepare for the worst” actually helps patient expectations rather than hinders. A frank discussion about postoperative pain management options reassures patients and helps them to understand that relief is available. With the advent of newer management techniques, procedures are available which may allow for sophisticated postoperative strategies to handle any discomfort. Transdermal patches, epidural injections and new oral pain medications are but a few strategies which will allow the patient and the surgeon to sleep in the days and weeks following anorectal surgery. A preoperative consultation with a pain management specialist may be worth its weight in sleep. Beginning stool softeners prior to the operation may help in easing the pain of the first bowel movement.
Educating the Operating Team
Urinary retention is the bane of the anorectal surgeon. The discomfort of urinary retention adds to the pain from the operation. It is recommended that the operation be performed using a safe, but limited volume of intravenous fluids. Should retention be encountered following the operation, an attempt to void while sitting in a warm tub may be all that is necessary to achieve symptomatic relief. However, prolonged urinary retention may worsen matters and might be indicative of a more serious underlying problem. Patients should be instructed to contact their surgeon earlier rather than later in their course.
Educating the Surgeon
Another area of improvement has evolved through the efforts of surgeons and industry working together to develop less traumatic procedures. An example of this collaboration has been in the area of the hemorrhoidectomy. PPH (Procedure for Prolapse and Hemorrhoids), and THD (Transarterial Hemorrhoidal Dearterialization) have been shown to be associated with diminishing, but not vanishing, postoperative pain. Procedures such as these are performed proximal to the dentate line and result in less pain because of the paucity of pain fibers in this region. These procedures require careful patient selection, and are best suited for Stage II-III hemorrhoids with prolapse and a limited external hemorrhoidal component. When PPH and THD are compared with the Milligan-Morgan technique for Stage IV hemorrhoids, the duration and depth of pain following an excisional hemorrhoidectomy is typically longer and more severe. Although considered to be an advance in hemorrhoidal operations, the adoption of these newer techniques has been slow because special training is required.
Traditionally, multimodality and multidisciplinary pharmacological techniques have been used to help in the management of the patient’s recovery. Opioids have been a cornerstone in the management of postoperative pain. However, narcotics may be accompanied by numerous, well known side-effects such as nausea, vomiting, constipation, respiratory depression, ileus, itching, and dependence/tolerance. Adverse events related to opioids occur in 12% to 48% of patients (6). In the inpatient setting, opioid related adverse events account for a 3.3 day increase in the length of stay. Several options exist to help in decreasing the dependence on narcotics.
NSAIDS or acetaminophen have been shown to help with postoperative pain control. NSAIDS may be started prior to the operation and continued through the recovery period. Many studies have demonstrated a diminution in pain relief scores when up to 1,000mg of acetaminophen, 600mg of ibuprofen, or 10 mg of ketorolac were given immediately after surgery (7). The NSAIDS aid in reducing and managing the inflammatory response. Cyclooxygenase-2 inhibitors, ketamine, clonidine and steroids have also demonstrated benefit. Many surgeons have patients begin taking NSAIDS prior to the operation and continue to take the medication throughout the recovery period. As NSAIDS may be associated with postoperative bleeding, their use must be evaluated with a preoperative assessment of various patient risk factors.
Some institutions are utilizing gabapentin/pregabalin in fast-track recovery protocols for abdominal surgery. Several studies have demonstrated that administering 1,200 mg of gabapentin or 300 mg of pregabalin preoperatively yields a decrease in adjunctive narcotic requirements (8). Some surgeons will administer the medication for up to 2-3 days postoperatively. Larger doses have been associated with sedation and dizziness. There are no established studies evaluating the use of these medications following anorectal surgery. Anecdotal reports abound however, testifying to their effectiveness. This is an area ripe for larger, randomized trials.
Local Pain Control. The Basics.
Any anesthetic agent that is able to inhibit the excitatory process in the nerve ending will block the perception of pain. The nerve membrane is a lipid and protein structure. The two key elements in pain control are the anesthetic potency and duration of action. These are related to lipid and protein structure of the nerve membrane. Anesthetic potency is correlated with lipid solubility. Anesthetic duration is related to the degree of protein binding at the membrane level, with a longer duration of anesthesia being the result of a greater binding ability.
Both pH and the type and size of the nerve fibers also play a role in the anesthetic effects of various agents. Local anesthetics are more effective in more basic pH environments. Smaller nerves with lighter myelin coatings are more easily blocked than are larger, more heavily myelinated nerves. Pain is most commonly the first sensation to be blocked and the last to recover, followed by temperature sensation, touch and pressure.
Anesthetic agents can be degraded by hydrolysis or by enzymatic activity. As bupivicaine is metabolized most slowly, its anesthetic effects are longer lasting. Lidocaine is rapidly metabolized and is a short acting agent. These two drugs are the most common local anesthetic agents used in anorectal procedures.
Local anesthetics are used routinely and are extremely effective for completely blocking pain sensation intraoperatively. Administered in the form of a pudendal block, coupled with direct injections into the operative sites prior to beginning the operation, local anesthetics are also effective in managing pain in the postoperative setting. Their benefit however, is limited by their duration of effectiveness. Bupivicaine and lidocaine have established durations of action of less than 12 hours, even with the use of epinepherine. Because of this, there have been attempts to improve the duration profile of local anesthetics. Elastomeric pain pumps and catheter systems have been shown to help ameliorate the pain for several days postoperatively. Ideally, the pumps should deliver a steady dose of the anesthetic for one to seven days, depending on the size of the pump. However, there have been technical problems reported, including catheter dislodgement, and infections (9).
Epidural anesthesia is a reliable way to ensure a pain-free postoperative recovery. The catheters can remain in place for up to five days after a procedure. While most often used in the hospital setting, it is theoretically possible to use this type of system as an outpatient. Adoption of this technique has been hampered by the need for periodic infusion of the anesthetic, catheter dislodgement, various systemic side-effects and the potential for a delay in the diagnosis of a possibly serious, catheter-related infection.
The topical application of local anesthetics is of marginal and unpredictable efficacy.
A Leap Forward? More Basics
Liposomal depot formulations of bupivicaine have shown promise in the management of postoperative pain (10,11). Liposomes are laboratory-prepared, microscopic lipid bilayer membranes that encapsulate an aqueous core. A lipid bilayer is essentially a double thickness layer of phospholipid molecules. Each of the two layers is one molecule in thickness. This dual layer system is common in nature and serves to keep substances positioned where they are needed, thus preventing these substances (proteins or ions) from diffusing away from their target area. Cell membranes are composed of lipid bilayers.
The idea behind using a liposomal system is that the liposomes can be formulated into a multivesicular system, with the active anesthetic agent being held in each vesicle and slowly released to the target area over time. The anesthetic agent, bupivicaine, is not new; the delivery system is the apparent innovation. The anesthetic system is marketed under the name of Exparel®.
The mulitivesicular liposomal preparation theoretically results in a drug release pattern showing an increased stability and a prolonged duration of medication release. The pharmacokinetics result in a 7-fold increase in the t-max, and a 9.8 times increase in the t-1/2 life of the mediation. The manufacturer states that the medication has duration of up to 72 hours of delivery and effectiveness. The onset of action is immediate, as there is free bupivicaine in the solution along with the microvesicular preparation.
Recent FDA approval of the liposomal bupivicaine formulation has been granted for use in hemorrhoidectomies and bunionectomies. Gorfine et al performed a mulit-center, double blinded, placebo-controlled study in patients undergoing hemorrhoidectomies (12). The use of 300 mg of the liposomal bupivicaine was compared to a saline placebo, and evaluated over 72 hours. Pain intensity scores were significantly lower in the extended-release group vs. the placebo group. At 12 hours, 59% of patients in the extended-release group were opioid-free, compared with 14% in the placebo group. At 72 hours, 28% were opioid-free, compared 10% in the placebo group. In patients requiring opioids, median time to first use was 14.3 hours in the liposomal bupivicaine group compared with 1.2 hours for the placebo group. Ultimately, a 30% reduction in cumulative pain and a 45% reduction in the opioid consumption were seen in the study. The safety profile of the formulation has been studied in dose levels of 66mg to 532mg (with the FDA dose approved at 266 mg), and cardiac safety has been demonstrated in supratheraputic doses as high as 665mg in healthy volunteers.
Studies evaluating extended release bupivicaine in the setting of open and laparoscopic colectomies, ileostomy reversal, breast augmentation, inguinal hernia repairs, and total knee replacement demonstrated similar favorable results (13-17). It seems that the medication may be of benefit in many procedures requiring the use of local anesthesia.
Liposomal bupivicaine comes in single use 20 cc vials containing 266 mg of bupivicaine which must be stored between 36 and 46 degrees Fahrenheit. A temperature indicator will change from green to white if the medication has been exposed to excessively low or high temperatures. The medication may be stored at room temperature for up to 30 days.
The liposomal structure may be altered if the preparation is exposed to lidocaine or other anesthetics and should not be mixed with other preparations. Liposomal bupivicaine may used without dilution or may be mixed with up to 280 cc’s of preservative-free, sterile saline. It should not be diluted with water or any other hypotonic solution which might disrupt the delivery system. The profile of side effects for liposomal bupivicaine is that of the parent drug, bupivicaine, and the surgeon must be familiar with the adverse effect profile and treatment of bupivicaine-related adverse reactions.
The Anecdote About the Antidote. Curbside Consultations and Operating Room Experience.
The use of liposomal bupivicaine has been the topic of many surgical lounge discussions and intra-office surgical debates. As Exparel® is expensive, much thought has gone in to the decision to purchase and use it clinically. We have discussed this topic with colleagues, with drug representatives and amongst the surgeons in our group. We decided to try liposomal bupivicaine in our own, unscientific trial. Our results have been impressive.
Our protocol has been to administer the medication in the more dilute form using a pudendal block and a local infiltration in the perianal area and around the anal verge. The medication is typically diluted 2:1 and infiltrated just after the surgical time out is performed, with the patient under intravenous sedation. We have not experienced any anesthetic failures during the intraoperative period. At the conclusion of the procedure, a bolus of 30 mg of ketorolac is given by the intravenous route to those patients without any contraindications to its use. In the first three postoperative days, no oral or other adjunctive medications are used unless the patient feels the need for supplemental pain relief. After three days, patients are given ketorolac, 10 mg. orally every six hours for 12 doses. To date, 100% of our patients have been almost pain free for the entire six day period. Opioid use has been minimal both during the six day postoperative period and after the six day period. In all of our cases, the operative anorectal procedures have been extensive. We have not used liposomal bupivicaine in procedures that we considered to be of a minor nature.
Our patients have not experienced any adverse effects.
The Tale of the Traveling Salesman
Perhaps most interesting is our patient, a traveling salesman. He was due to leave town immediately after his office visit, for a three day, important sales presentation. The pain from his acute thrombotic hemorrhoid had almost crippled him. Because of his impending trip, he was not amenable to surgical drainage or removal. He was desperate for pain relief and refused to consider canceling his trip. He was offered an injection of liposomal bupivicaine and he agreed to try it. The medication was diluted to 40 cc’s. and the local injection was made through a 25 gauge needle around and deep to the thrombotic hemorrhoid. The injection of most local anesthetics in an awake patient is uncomfortable at best and the salesman’s expletives attested to this. Fortunately, the salesman’s office visit was at the end of the day when no other patients were nearby to his rather loud comments during the injection. However, he left the office without any pain. He returned three days later in a mood bordering on euphoria. He had had no pain since the initial injection. Unfortunately for him, he lost the sale. Because he had incorrectly accounted for the time zone change during his flight, he arrived one hour late for his presentation and was denied a chance to make his pitch. This time however, his expletives were directed at himself rather than the Exparel®. Surgeons cannot fix everything.
Antidote or Anecdote? Judge for Yourself.
We have been happy with our results to date. Patients have been happy with their results to date. However, our trial is only anecdotal. While supported by clinical trials, our results may not be the same as those of other surgeons. Time and experience will be the final arbiter of clinical efficacy. But liposomal bupivicaine, while expensive, may be a useful medication in combating pain following anorectal operations.
THE AUTHORS HAVE NO FINANCIAL RELATIONSHIPS WITH ANY OF THE MANUFACTURERS OF ANY OF THE DRUGS MENTIONED IN THIS REVIEW.
- Cullen KA, Hall MJ, Golosinkiy A. Ambulatory surgery in the United States, 2006. Natl Health Stat Report. 2009;1-25.
- Coley KC, Williams BA, DaPos SV, Chen C, Smith RB. Retrospective evaluation of unanticipated admissions and readmissions after same day surgery and associated costs. J Clin Anesth. 2002;14:349-353.
- Warfield CA, Kahn CH. Acute pain management. Programs in US hospitals and experiences and attitudes among US adults. Anesthesiology. 1995;83:1090-1094.
- Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97:534-540.
- Gan TJ, Habib AS, White W, Miller T. Postoperative pain continues to be undermanaged [abstract]. Presented at: Annual Fall Pain Meeting and Workshops of the American Society of Regional Anesthesia and Pain Medicine; November 15-18, 2012; Miami Beach FL.
- Oderda G, Gan T. Effect of opioid-related adverse events on outcomes in selected surgical patients. J Pain Palliat Care Pharmacother. 2012. Submitted.
- Pyati S, Gan TJ. Perioperative pain management. CNS Drugs. 2007;21:185-211.
- Dauri M, Faria S, Gatti A, Celidonio L, Carpenedo R, Sabato AF. Gabapentin and pregabalin for the acute post-operative pain management. A systematic-narrative review of the recent clinical evidences. Curr Drug Targets. 2009 Aug;10(8):716-33.
- Brown SL, Morrison AE. Local anesthetic infusion pump systems adverse events reported to the Food and Drug Administration. Anesthesiology. 2004;100:1035-1037.
- Chahar P, Cummings KC, Liposomal bupivicaine: a view of a new bupivicaine formulation. Journal of Pain Research. 2012;5:257-264.
- Candiotti K, Liposomal bupivicaine: An innovative nonopioid local anesthetic for the management of postsurgical pain. Pharmacotherapy 2012;32:19S-26S.
- Gorfine SR, Onel E, Patou G, Krivokapic ZV. Bupivicaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing a hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 2011;54:1552-1559.
- Smoot JD, Bergese SD, Onel E, Williams HT, Hedden W. The efficacy and safety of DepoFoam bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammoplasty: a randomized, double-blind, active-control study. Aesthet Surg J 2012;32:69–76.
- Minkowitz HS, Onel E, Patronella CK, Smoot JD. A two-year observational study assessing the safety of DepoFoam bupivacaine after augmentation mammoplasty. Aesthet Surg J 2012; 32(2):186–93.
- White PF, Schooley G, Ardeleanu M. Analgesia following a single administration of depobupivacaine intraoperatively in patients undergoing inguinal herniorraphy: preliminary dose-ranging studies. Presented at the Annual Meeting of the International Anesthesia Research Society, San Diego, CA, March 14–17, 2009.
- Langford RM, Chappell GM, Karrasch JA. A single administration of depobupivacaine intraoperatively results in prolonged detectable plasma bupivacaine and analgesia in patients undergoing inguinal hernia repair. Presented at the 62nd Postgraduate Assembly in Anesthesiology, New York, NY, December 12–16, 2008.
- Bramlett KW, Jones RK, Pink M, Pink T. A single administration of depobupivacaine intraoperatively provides analgesia and reduction in use of rescue opiates compared with bupivacaine HCl in patients undergoing total knee arthroplasty [poster]. Presented at the XXXVI Biennial World Congress of the International College of Surgeons, Vienna, Austria, December 3–6, 2008.