This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hong, D. Articles by Flood, P. Search for Related Content PubMed PubMed Citation Articles by Hong, D. Articles by Flood, P. Related Collections Pain Medicine Pain Pharmacology

---

ANALGESIA

Transdermal Nicotine Patch for Postoperative Pain Management: A Pilot Dose-Ranging Study

From the Department of Anesthesiology, Columbia University Medical Center, New York City, New York.

Abstract

BACKGROUND: Nicotine has been shown to be antinociceptive in the postoperative period in animal studies. Human studies with nasal nicotine sprays have had mixed results, possibly due to variability in pharmacokinetics and potential patient variables such as exposure to nicotine in tobacco smokers. In this pilot study, we examined the analgesic effect of a transdermal nicotine patch applied before surgery in nonsmokers.

METHODS: We conducted a randomized, double-blind, prospective placebo-controlled trial of 40 subjects, undergoing general surgery that required postoperative patient-controlled analgesia and an overnight hospital admission. Immediately before surgery, a transdermal nicotine patch containing 0, 5, 10, or 15 mg was applied. The primary outcome variable was pain report using a numerical rating scale (NRS) in the first hour after surgery and over the next 5 days. Secondary outcomes were pain medication use, hemodynamic values, nausea, and sedation.

RESULTS: Patients treated with nicotine reported lower pain scores when compared with those treated with placebo during the first hour after surgery (P = 0.003, average NRS decrease = 1.4, 95% CI = 0.3–2.6) and for 5 days after surgery (P = 0.03, average NRS decrease = 1.0, 95% CI = 0.1–1.9). There was no increased benefit of nicotine with doses larger than 5 mg. There was a trend suggesting decreased pain medicine use, increased nausea, decreased tachycardia, and slightly decreased systolic blood pressure in the nicotine groups, but these values did not reach significance.

CONCLUSIONS: Transdermal nicotine, 5–15 mg, reduced postoperative pain scores but failed to decrease the need for opioid analgesics or opioid-related side effects after general surgical procedures.

Despite the widespread adoption of patient-controlled analgesia (PCA) and its superiority over intermittent IM injection of analgesics, acute postoperative pain continues to be poorly controlled. As many as 70%–80% of patients experience moderate to severe pain in the postoperative period despite pharmacological management.1–3 The use of non-opioid medications such as nonsteroidal antiinflammatory drugs can improve pain control and decrease morphine use and opioid-related side effects, but carries serious pro- and anticoagulant side effects.4 There is room for improvement in the practice of postoperative pain management and the development of novel adjuvant pain medications.

Nicotinic agonists have been shown to have antinociceptive properties in several animal models5 via activation of descending central inhibitory pain pathways,6–8 and via peripheral action.9 Studies in volunteers have demonstrated that nicotine has analgesic properties in such diverse modalities as cold pressor pain,10,11 and pain induced by electrical shock.12 Nicotine may also have an analgesic role specific to the paradigm of postoperative pain after use of an inhaled anesthetic. Inhaled anesthetics have been shown to produce hyperalgesia at minimal concentrations in animals,13 and nicotine reverses this hyperalgesic effect.14 Human clinical studies have demonstrated that administration of an intranasal nicotine spray results in decreased pain scores and opioid sparing after gynecological surgeries.15

The aim of this randomized, double-blind, clinical trial was a pilot study to determine whether nicotine administered with a transdermal patch has an analgesic effect after surgery. We hypothesized that nicotine administered with a patch can provide adjuvant analgesia in the postoperative period.

METHODS

This double-blind, randomized, prospective, placebo- controlled trial was designed to evaluate the effects of nicotine patches on postoperative pain and was approved by the IRB of the Columbia University Medical Center. Written consent was obtained from all subjects.

Subjects
Forty patients who did not smoke tobacco, 20 men and 20 women, were enrolled and followed for 5 days after surgery. All subjects were older than 18-yr-of-age and scheduled to undergo general surgical procedures including pelvic and abdominal surgeries that were either open or laparoscopic with the use of a volatile anesthetic. Inclusion criteria were planned overnight stay in the hospital and the use of postoperative PCA. Exclusion criteria were current or recent smoking history within the last 6 mo, a history of uncontrolled hypertension, myocardial disease, stroke, respiratory disease, pregnancy, chronic pain, or use of chronic pain medications and the use of spinal or epidural anesthesia during the operation.

Study Design
Ten patients (5 men and 5 women) were assigned by a computer-generated randomization table to each of four treatment groups: 0, 5, 10, and 15 mg of nicotine. The patient, investigator, and health care staff were blinded to the treatment group. Nicotine was delivered with a combination of three transdermal patches (Nicotrol 10 cm², containing 5 mg/16 h, Ellerslie, Auckland; New Zealand) or identical placebo patches custom-made by 1-800-Patches (Salt Lake City, UT). The patches were applied to glaborous skin away from the surgery site, immediately before induction of anesthesia. The patches were removed at bedtime on the same night of surgery.

All patients were anesthetized with a volatile anesthetic and were given 0.1–0.2 mg/kg morphine or the equivalent of another narcotic during the procedure, but the anesthetic was not otherwise standardized. PCA was administered according to standard postoperative protocol at this institution, which consists of parenteral morphine set at 1 mg demand dose only, 6-min lockout, and 10 mg hourly limit. There were allowances for 3 mg morphine boluses for breakthrough pain to a limit of 15 mg/h. The demand dose could be increased to 1.5 mg for inadequately treated pain. Fifteen minutes after tracheal extubation, and every 15 min for the next hour, a research associate asked the patients to assess their pain on a numerical rating score scale (NRS) (0 = no pain, 10 = the worst pain imaginable). Nonsteroidal antiinflammatory drugs were used only for breakthrough pain at the request of the clinical team. We recorded concurrent measurements of pain medication used, sedation on the Observer's Assessment of Alertness/Sedation scale, occurrence of nausea, antinausea medications used, and hemodynamic values. Arterial blood pressure was measured using a noninvasive cuff and heart rate was monitored using a pulse oximeter during the first hour after surgery. During the course of their hospital stay, the PCA was discontinued and the patient given alternative oral pain medications at the discretion of the surgical team.

To characterize long-term pain response, all patients were followed for 5 days postoperatively. Subjects were interviewed at 24-h intervals in the hospital or at home via telephone by the investigators who requested a NRS pain score. The amount of pain medication used over each 24-h interval was recorded. For ease of comparison in the analysis, all opioid pain medications were converted to equianalgesic milligrams of parenteral morphine according to standard conversion factors in Goodman and Gilman 11th edition.16 The equianalgesic values in this table were consistent with ranges determined by a recent literature review.17

Statistical Analysis
The primary outcome variable was NRS at 1-h based on our previous trial with nicotine nasal spray.15 The sample size for this trial was determined to provide 80% power to detect a change of 1.6 NRS points with P < 0.05. Patient demographics were analyzed using Student's t-test and Fisher's exact test (GraphPad InStat 3.06, San Diego, CA). The nonlinear mixed effects model (NONMEM) software (Globomax, Ellicott City, MD) was used to analyze the NRS pain reduction and pain medication use over time. NONMEM was used to produce a regression model for the data with and without a fixed effect of nicotine on pain, and statistical significance was determined using the ² likelihood ratio test on the resulting objective functions. The use of NONMEM was chosen over a repeated measures analysis of one way variance or general linear model regression (SPSS 14.0 Graduate Pack, Chicago IL), because of the unbalanced numbers between the control and pooled nicotine groups and incomplete data points for three patients due to surgical complications over 5 days. Sample NONMEM code used for the analysis is included in the Appendix. The hemodynamic data were complete for all patients over the 1 h observation period and were analyzed with a repeated measures general linear model analysis in SPSS (Graduate Pack, version 14.0, Chicago, IL). The side effect data were analyzed with a ² trend test (GraphPad InStat 3.06, San Diego, CA) for the incidence of nausea and repeated measures analysis of one way variance for sedation and use of nausea medications. All values are reported as means (±se).

RESULTS

Forty patients were enrolled in the study. In the control group, one patient was not followed after 2 days postoperatively because of a second surgery for placement of a gastrostomy tube. Another patient in the control group was not followed after 3 days postoperatively because of reexploration for bleeding. One patient in the 15 mg nicotine group was not followed after 3 days, also because of reoperation for bleeding.

There were no significant differences between the placebo and nicotine groups with respect to age, gender, weight, number of laparoscopic versus open procedures, duration of surgery, or intraoperative opioid use (Table 1). All subjects were given fentanyl as a part of their anesthetic and all but three were given morphine intraoperatively. The three subjects who did not receive morphine were given hydromorphone during their anesthetic.

Patients receiving nicotine had lower postoperative NRS pain scores during the first hour compared with the control group (Fig. 1). The magnitude of this reduction was 1.4 NRS points with a 95% confidence interval of 0.3–1.9 (P = 0.003). The reduction in NRS pain scores in the nicotine group persisted for 5 days. The average magnitude of pain reduction during the 5 days was 1.0 NRS points (95% CI = 0.1–1.9, P = 0.034). The analgesic effect of nicotine was not significantly enhanced with higher doses of nicotine (Fig. 2).

View larger version (8K): [in this window] [in a new window]   Figure 1. Numerical Pain Scale (NRS) Score with and without nicotine. (A) In the hour after surgery, there was an average decrease in pain of 1.4 NRS points (P < 0.01, 95% CI = 0.3–1.9) in the nicotine group over the control group. (B) This analgesic effect persisted for 5 days with an average decrease of 1.0 NRS points (P < 0.05, 95% CI = 0.1–1.9). Data are mean ± se.

View larger version (12K): [in this window] [in a new window]   Figure 2. Subgroup analysis effect of nicotine dose on pain report mean (±se) numerical rating scale pain scores (A) 1 h and (B) 5 days after surgery. The reduction in postoperative pain due to nicotine did not show a significant dose dependence.

In the first hour, there was a trend to reduced opioid use in the nicotine group but this did not reach statistical significance. There was no statistically significant difference between the nicotine and control groups in amount of opioids used (Fig. 3). In the control group, six subjects were given ketorolac for breakthrough pain in the first day and five subjects in each treatment group. There was no difference in either heart rate or arterial blood pressure between the two groups during the first hour after surgery (Fig. 4). There was also no difference in sedation between the nicotine or control groups in sedation as measured by Observer's Assessment of Alertness/Sedation Scale score. There were more incidents of nausea and antiemetic use with nicotine doses 10 and 15 mg/d, but this effect did not reach statistical significance (Table 2).

View larger version (17K): [in this window] [in a new window]   Figure 3. Pain medication used 5 days after surgery. All opioid pain medications were converted to equivalent units of milligram of morphine per kilogram per hour. There was no significant difference between patients who received the nicotine patch and the control group. Data are mean ± se.

View larger version (10K): [in this window] [in a new window]   Figure 4. Hemodynamic response in the first hour after surgery. (A) There was no significant difference in systolic or diastolic blood pressure in the patients treated with nicotine compared with the control group. (B) There was no difference in the postoperative heart rate between groups. Data are mean ± se.

DISCUSSION

In this randomized, double blind, placebo-controlled pilot study, we demonstrated that preoperative application of a transdermal nicotine patch had an analgesic effect. The decrease in pain at 1 h was significant clinically as the magnitude of analgesia was comparable to that achieved by current regimens of adjuvant analgesics.18,19 It is unusual in studies of potential analgesic adjuvants for the pain report to be decreased. More commonly, there is sparing of rescue drug use but pain report is the same. This finding underscores the bimodal nature of opioid titration that makes adjuvant analgesics desirable. Patients will self administer opioids to relieve pain, but not always to optimum pain treatment because of other considerations, including side effects.

This pilot study provides several advantages over previous studies by Flood and Daniel15 and by Cheng20 that evaluated intranasal nicotine for analgesic effects after gynecological surgeries. First, we showed that the transdermal nicotine patch was an effective treatment modality. We believe the transdermal patch is superior to the intranasal spray as a nicotine delivery vehicle because it is not noxious for patients to use and results in much less variability in plasma nicotine levels.21 Second, this trial showed that the analgesic effect was also present in general surgeries with a nonstandardized volatile anesthetic-based regimen. Third, our study included both men and women patients. Multiple factors complicate the interaction between pain, gender, and antinociception. Women have higher baseline pain scores after surgery, estrogen may modulate the pain response,22 and both human and animal studies have found gender-specific differences on the analgesic effect of nicotine.12,23 Although our study was not powered for a subgroup analysis of gender differences, we showed that nicotine was effective in a combined cohort of men and women patients.

In our first study, we showed that the analgesic effect of a single bolus of nicotine nasal spray persisted at 24 h.15 Our current trial was designed with a longer follow-up period in order to determine the duration of effect. We found that the analgesic effect of nicotine did not diminish during the study period of 5 days after surgery. It is unlikely that the long-term analgesia benefit was due to a pharmacological effect. The treatment was applied only during the first day and the transdermal patch reaches a maximum plasma nicotine concentration at approximately 4 h24 and has a typical single dose half-life of 3 h after patch removal.25 Nociception is a plastic process and improved perioperative control of pain may prevent central and peripheral sensitization to pain.26,27 Nicotinic agonists have also been shown to have antiinflammatory effects on macrophages28 and it is possible that the prolonged analgesic effect of nicotine may be due to inhibition of the slower process of inflammatory pain.

When the patients were stratified by nicotine dosage in our trial, increasing the dose of nicotine beyond 5 mg/d did not have any statistically significant additional analgesic benefit. It is possible that 5 mg/d is the maximum effective dose, but this was not a definitive finding because our study was not powered for this subgroup analysis.

In addition to the lower pain scores, there was a trend towards decreased opioid use over the first hour and first postoperative day in the nicotine group, but this difference did not reach statistical significance. Opioid use is much more variable than pain score; despite a reduction of nearly one-third in morphine use over the first hour, our study was under-powered to definitively detect a reduction. A larger trial would be required to address these questions.

In terms of adverse effects of nicotine, the two main concerns were adrenergic stimulation and nausea and vomiting.29 Our study did not find an increase in arterial blood pressure or heart rate. We hypothesize that autonomic stimulation may have been offset by the fact that patients treated with nicotine were in less pain. There was a trend toward increased incidence of nausea and increased use of rescue antiemetic medication with nicotine doses of 10 mg/24 h and larger, but this increase was not statistically significant. This study was not powered to study nausea by dose, but minimum side effects were incurred by using the lowest dose of 5 mg/24 h without loss of analgesic effect.

A limitation of our study was that we did not measure plasma nicotine levels, which would have given a more precise picture of the pharmacokinetics of nicotine and pain and a potential explanation of variability. Another limitation was the small number of patients enrolled, which limited our power to study the incidence of rare cardiovascular events or to analyze subgroup differences such as gender. One confounding variable that we avoided in our study was smoking history and the possible effect of chronic nicotine tolerance. We are currently conducting a parallel study in a cohort of smokers to address these questions.

In conclusion, this pilot study demonstrated the feasibility and potential clinical utility of using transdermal nicotine as an analgesic adjuvant for postoperative pain in men and women. For future studies, our findings of a reasonable dosage range, minimal side effect profile, and characterization of the natural variance of pain reduction will enable us to design a larger multicenter trial for more rigorous confirmation of our results.

APPENDIX: SAMPLE NONMEM CODE (ANALYSIS OF 1 HOUR PAIN SCORES WITH FIXED NICOTINE EFFECT)

$PROB VAS Scores

$DATA NRS1HR.txt

$INPUT ID ACT TIME VAS DV MDV

; ACT 1 for Nicotine, 0 for control

; VAS is the pain score

$PRED

IF(ACT.EQ.1) THEN DRUG THETA (5) ELSE DRUG=0 ENDIF

IF (TIME.EQ.0.25) TY=THETA(1)DRUGETA(1); 15 min

IF (TIME.EQ.0.5) TY = THETA(2)DRUGETA(1); 30 min

IF (TIME.EQ.0.75) TY = THETA(3)DRUGETA(1); 45 min

IF (TIME.EQ.1) TY = THETA(4)DRUGETA(1); 60 min

IPRD = TY Y = TY+EPS(1)

$THETA

(0, 6, 10); Theta 1: 15 min

(0, 6, 10); Theta 2: 30 min

(0, 4, 10); Theta 3: 45 min

(0, 3, 10); Theta 4: 60 min

2; Theta 5: Reduction in VAS by nicotine

$OMEGA

1; Between subject variability, first hour

$SIGMA

3; Residual variability

$ESTIMATION MAX = 1000 PRINT = 1 NOABORT METHOD = 1 SIG = 3

$TABLE ID TIME DRUG ACT IPRD

Footnotes

Accepted for publication November 15, 2007.

Dr. Flood is the wife of Dr. Shafer, Editor-in-Chief of Anesthesia & Analgesia. This manuscript was handled by Spencer Liu, Section Editor of Pain Medicine, and Dr. Shafer was not involved in any way with the editorial process or decision.

Address correspondence and reprint request to Dr. Pamela Flood, Department of Anesthesiology, Columbia University, 630 West 168th St., New York City, NY 10032. Address e-mail to pdf3{at}columbia.edu.

REFERENCES

1. Thomas T, Robinson C, Champion D, McKell M, Pell M. Prediction and assessment of the severity of post-operative pain and of satisfaction with management. Pain 1998;75:177–85[Web of Science][Medline]
2. Owen H, McMillan V, Rogowski D. Postoperative pain therapy: a survey of patients' expectations and their experiences. Pain 1990;41:303–7[Web of Science][Medline]
3. Svensson I, Sjostrom B, Haljamae H. Assessment of pain experiences after elective surgery. J Pain Symptom Manage 2000;20: 193–201[Web of Science][Medline]
4. White PF. The role of non-opioid analgesic techniques in the management of pain after ambulatory surgery. Anesth Analg 2002;94:577–85[Free Full Text]
5. Flores CM. The promise and pitfalls of a nicotinic cholinergic approach to pain management. Pain 2000;88:1–6[Web of Science][Medline]
6. Iwamoto ET, Marion L. Adrenergic, serotonergic and cholinergic components of nicotinic antinociception in rats. J Pharmacol Exp Ther 1993;265:777–89[Abstract/Free Full Text]
7. Bannon AW, Decker MW, Holladay MW, Curzon P, Donnelly-Roberts D, Puttfarcken PS, Bitner RS, Diaz A, Dickenson AH, Porsolt RD, Williams M, Arneric SP. Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors. Science 1998;279:77–81[Abstract/Free Full Text]
8. Bitner RS, Nikkel AL, Curzon P, Donnelly-Roberts DL, Puttfarcken PS, Namovic M, Jacobs IC, Meyer MD, Decker MW. Reduced nicotinic receptor-mediated antinociception following in vivo antisense knock-down in rat. Brain Res 2000;871:66–74[Web of Science][Medline]
9. Caggiula AR, Epstein LH, Perkins KA, Saylor S. Different methods of assessing nicotine-induced antinociception may engage different neural mechanisms. Psychopharmacology (Berl) 1995;122:301–6[Medline]
10. Fertig JB, Pomerleau OF, Sanders B. Nicotine-produced antinociception in minimally deprived smokers and ex-smokers. Addict Behav 1986;11:239–48[Web of Science][Medline]
11. Pomerleau OF, Turk DC, Fertig JB. The effects of cigarette smoking on pain and anxiety. Addict Behav 1984;9:265–71[Web of Science][Medline]
12. Jamner LD, Girdler SS, Shapiro D, Jarvik ME. Pain inhibition, nicotine, and gender. Exp Clin Psychopharmacol 1998;6:96–106[Web of Science][Medline]
13. Zhang Y, Eger EI II, Dutton RC, Sonner JM. Inhaled anesthetics have hyperalgesic effects at 0.1 minimum alveolar anesthetic concentration. Anesth Analg 2000;91:462–6[Abstract/Free Full Text]
14. Flood P, Sonner JM, Gong D, Coates KM. Isoflurane hyperalgesia is modulated by nicotinic inhibition. Anesthesiology 2002;97: 192–8[Web of Science][Medline]
15. Flood P, Daniel D. Intranasal nicotine for postoperative pain treatment. Anesthesiology 2004;101:1417–21[Web of Science][Medline]
16. Gutstein HBA, Huda. Opioid analgesics. In: Brunton LL, ed. Goodman and Gilman's the pharmacological basis of therapeutics. New York, NY: McGraw Hill, 2006
17. Patanwala AE, Duby J, Waters D, Erstad BL. Opioid conversions in acute care. Ann Pharmacother 2007;41:255–66[Abstract/Free Full Text]
18. Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology 2005;103: 1296–304[Web of Science][Medline]
19. Turan A, White PF, Karamanlioglu B, Memis D, Tasdogan M, Pamukcu Z, Yavuz E. Gabapentin: an alternative to the cyclooxygenase-2 inhibitors for perioperative pain management. Anesth Analg 2006;102:175–81[Abstract/Free Full Text]
20. Cheng SS, Yeh J and Flood P. Anesthesia Matters: patients anesthetized with propofol have less postoperative pain than those anesthetized with isoflurane. Anesth Anal 2008;106:264–9[Abstract/Free Full Text]
21. Benowitz NL, Zevin S, Jacob P III. Sources of variability in nicotine and cotinine levels with use of nicotine nasal spray, transdermal nicotine, and cigarette smoking. Br J Clin Pharmacol 1997;43:259–67[Web of Science][Medline]
22. Fillingim RB, Ness TJ. Sex-related hormonal influences on pain and analgesic responses. Neurosci Biobehav Rev 2000;24:485–501[Web of Science][Medline]
23. Girdler SS, Maixner W, Naftel HA, Stewart PW, Moretz RL, Light KC. Cigarette smoking, stress-induced analgesia and pain perception in men and women. Pain 2005;114:372–85[Medline]
24. Fant RV, Henningfield JE, Shiffman S, Strahs KR, Reitberg DP. A pharmacokinetic crossover study to compare the absorption characteristics of three transdermal nicotine patches. Pharmacol Biochem Behav 2000;67:479–82[Web of Science][Medline]
25. Gupta SK, Okerholm RA, Coen P, Prather RD, Gorsline J. Single- and multiple-dose pharmacokinetics of Nicoderm (Nicotine Transdermal System). J Clin Pharmacol 1993;33:169–74[Abstract]
26. Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol 2006;19:551–5[Medline]
27. Ong CK, Lirk P, Seymour RA, Jenkins BJ. The efficacy of preemptive analgesia for acute postoperative pain management: a meta-analysis. Anesth Analg 2005;100:757–73[Abstract/Free Full Text]
28. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al-Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384–8[Web of Science][Medline]
29. Greenland S, Satterfield MH, Lanes SF. A meta-analysis to assess the incidence of adverse effects associated with the transdermal nicotine patch. Drug Saf 1998;18:297–308[Web of Science][Medline]

This article has been cited by other articles:

				L. C. Olson, D. Hong, J. S. Conell-Price, S. Cheng, and P. Flood A Transdermal Nicotine Patch Is Not Effective for Postoperative Pain Management in Smokers: A Pilot Dose-Ranging Study Anesth. Analg., December 1, 2009; 109(6): 1987 - 1991. [Abstract] [Full Text] [PDF]

				N. L. Benowitz Nicotine and Postoperative Management of Pain Anesth. Analg., September 1, 2008; 107(3): 739 - 741. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hong, D. Articles by Flood, P. Search for Related Content PubMed PubMed Citation Articles by Hong, D. Articles by Flood, P. Related Collections Pain Medicine Pain Pharmacology