EFFECT OF NON-STEROIDAL ANTIINFLAMMATORY DRUGS (NSAIDS) AND TRAMADOL ON POST CAESAREAN SECTION PAIN IN INITIATION OF LACTATION

BACHELOR OF PHARMACY (HONS) INTERNATIONAL MEDICAL UNIVERSITY (IMU)

Abstract Early initiation of lactation boosts infant health and immune system and allows mothers to bond with their infant. This process may be delayed in new mothers whose post-partum pain is not managed effectively. Women who undergo Caesarean deliveries typically receive post-operative analgesia either in oral or intramuscular form to manage their pain. Current hospital protocol recommends prescribing oral analgesia to post-Caesarean women on the second day after surgery however no fixed

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guidelines or recommendations are in place in terms of type of oral analgesia prescribed. This cohort study aims to determine if there are significant differences in terms of time to first initiate unassisted lactation between mothers who receive Mefenamic acid, Celecoxib or Tramadol. First unassisted lactation is defined as “the baby suckling at the breast directly for the first time after birth, supported only by the mother and without assistance”. 121 post-Caesarean women were recruited into this study, who received either Mefenamic acid, Celecoxib or Tramadol within the first 12 hours postsurgery. They are then interviewed regarding the time taken to first initiate unassisted lactation. The results of the study showed that all three medications were similar in terms of time taken by new mothers to initiate unassisted lactation. The choice of oral medications did not significantly alter the time taken to first initiate unassisted lactation in post-Caesarean women.

1.0 Introduction Early initiation of lactation is integral in building a baby’s innate reflexes, allows emotional bonding between infant and mother, helps keep the baby warm, and reduces post-partum bleeding in new mothers[1]. Early initiation of breastfeeding, especially in the neonatal period, also plays an important role in reducing infant mortality[2]. It is with these concerns in mind that it is pertinent to find the most effective pain management regime to allow new mothers to be able to begin breastfeeding early.

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Initiation of lactation is most successful when a mother is physically and psychologically prepared for breastfeeding[2]. Proper post-operative pain management is important to allow the mother to be alert and energetic enough to be able to provide care to their infant and to breastfeed their infant[3]. In 2009, Khan et all found that post-operative analgesia ensured that patients were pain-free and enabled early initiation of lactation in post-partum women[4]. According to the Academy of Breastfeeding Medicine Clinical Protocol #15: Analgesia and Anesthesia for the Breastfeeding Mother, post-partum pain that is not adequately managed leads to an increased risk of post-partum depression as well as poor psychological outcomes that leads to a negative effect on breastfeeding[5]. Effective post-operative pain management in post-Caesarean women leads to improved outcomes in terms of improving mobility, early recovery and the need for supplemental analgesia [3,6,7]. Pain is a major concern in postoperative care, especially in women undergoing Caesarean section because it may impair the recovery process as well as affect the mothers’ ability to care for her infant[3]. Administering analgesia to new mothers reduces the pain from the surgical scar and also facilitates early recovery[8]. Postpartum pain that is not managed properly can inhibit the ability of new mothers to initiate early lactation.[4-6], thus allowing new mothers to start nursing their newborn child earlier and to be discharged from hospital sooner.

Mersky in 1986 defined pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.[9] Pain is universally felt, but it is very subjective and studies by Taverner[10] in 2005 as well as Bendelow[11] in 2008 have shown that pain differs between each individual subject. Each individual has a different predisposition
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towards pain, and perception of pain can be affected by gender, emotional well-being, culture, religion, past experience as well as age[10,11].

In this cohort study, we aim to compare the efficacy of different analgesics in the management of pain in post-Caesarean women in terms of initiation of unassisted lactation. Current hospital policy for post-Caesarean pain management is IM pethidine every 6 hours for the first 24 hours, followed by an oral analgesia on day 2, to be continued until patient is discharged. Three oral analgesics are compared in this cohort study, Mefenamic acid, Celecoxib and Tramadol.

1.1 Mechanisms of pain The mechanisms of pain can generally be divided into central and peripheral pain. Peripheral pain arises from surgical trauma or a noxious stimulus that stimulates the release of inflammatory mediators such as prostaglandin which directly sensitizes the nociceptive receptors to produce primary hyperalgesia. Pain after Caesarean delivery may have two components; pain that arises from the wound itself (somatic pain) and pain arising from the uterus (visceral pain). Sensitization that occurs in the central nervous system is referred to as central pain, and is also sometimes known as neurogenic pain[12].

Figure 1: Mechanisms of Pain

NSAIDs alleviate mild to moderate peripheral pain. They work primarily by inhibiting the formation of cyclooxygenase (COX) that is responsible for synthesis of
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prostaglandins from arachidonic acid. Prostaglandins are mediators of inflammation, and the presence of prostaglandins leads to inflammation and the subsequent peripheral sensation of pain. Both Mefenamic acid and Celecoxib reversibly inhibit the enzyme, which results in the decrease in prostaglandin synthesis. This decrease in prostaglandins reduces the sensitivity of peripheral pain receptors to pain impulses at the site of inflammation and trauma[13].

Cyclooxygenase is comprised of two isoforms, COX-1 which is responsible for normal physiologic functions in the gastrointestinal tract, kidneys and platelets while the other isoform, COX-2 mediates inflammatory reactions.

Mefenamic acid is a non-selective cyclooxygenase inhibitor and works by inhibiting both cyclooxygenase-1(COX-1) and cyclooxygenase-2(COX-2). The inhibition of the constitutive COX-1 enzyme results in a higher incidence of side effects such as gastrointestinal ulcers, dyspepsia, gastrointestinal haemorrhage, gastrointestinal perforation, renal side effects such as sodium and water retention and/or hyperkalemia[14,15]. Mefenamic acid also inhibits platelet aggregation and prolongs bleeding time[6], which may be a problem in women who undergo Caesarean section. NSAIDs however has an advantage over opioids as they are associated with narcotic sparing effects such as improved respiratory function, reduction in nausea and vomiting, reduced sedation and there are also suggestions that NSAIDs may improve not only the quality but also the speed of recovery[16].

Figure 2: Mechanism of action of NSAIDs

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Celecoxib is a relatively new non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2(COX-2). Celecoxib is effective in alleviating inflammatory pain, but without the gastrointestinal side effects, renal side effects, platelet dysfunction[6] or liver toxicity[15] associated with conventional NSAIDs such as Mefenamic acid, therefore it may be a more suitable choice for management of postCaesarean section as it provides pain relief to new mothers with only minimal side effects to the mothers. Celecoxib is also particularly advantageous in situations where maternal bleeding is a concern, but this must be balanced with higher costs and possible cardiovascular risks to the mother.

Opioids inhibit pain by different mechanisms that do not involve cyclooxygenase or prostaglandins. Tramadol is an example of a centrally acting opioid analgesic that derives its central activity due to an analgesic binary mechanism of action. Tramadol acts as an agonist and binds to µ-opioid receptors that suppress the release of excitatory neuropeptide from C-fibers[6] as well as inhibiting the reuptake of noradrenaline and serotonin to interfere with central pathways that mediate pain[17]. Tramadol has proven efficacy in the management of chronic pain as well as postoperative pain[18] but it has a number of documented side effects such as pain, pruritus, nausea, vomiting, sedation and respiratory depression that can affect patients recovery[3,14].

Figure 3 Mechanism of action of Tramadol 1.2 Goals of post-operative pain management
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The importance of proper pain management is widely recognized. Pain is now deemed such an important facet of physical health that it is sometimes referred to as the fifth vital sign[19]. Patients undergoing surgical procedures such as Caesarean-section should receive the most effective pain-management strategies as it is important in allowing complete recovery.

The aim of post-operative pain management is to minimize and alleviate pain with the least side effects, to provide patient comfort and satisfaction and to allow early mobilization. Pain that is properly managed also reduces the occurrence of further complications and allows patients to recover faster with a less likelihood of development of neuropathic or chronic pain. Apart from that, effective pain management also reduces the cost of care and reduces morbidity and mortality[12,20]. Pain that is effectively managed is also linked to fewer incidences of pulmonary and cardiac complications, a reduced risk of deep vein thrombosis and subsequently reduced cost of care[12].

1.3 Why is this study needed? This cohort study aims to compare the breastfeeding outcomes of various approaches to pain management in Caesarean births. We aim to compare which oral analgesic
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(NSAIDs or opioids) allows mothers to begin initiating lactation sooner and subsequently determine which of the two NSAIDs involved in this cohort study provides better pain relief and allows new mothers to initiate lactation sooner.

Both opioids and NSAIDs provide pain relief post-surgically[21], however currently there are no fixed guidelines regarding the use of oral analgesia in managing postCaesarean pain. Opioids are effective in alleviating central pain and Tramadol is an example of an oral opioid that is used in local hospitals to manage post-Caesarean section pain. It is centrally acting and has proven efficacy in the management of chronic pain as well as post-operative pain. NSAIDs, on the other hand, provide excellent analgesia for mild to moderate peripheral pain. Oral non-narcotic agents such as ibuprofen are able to provide satisfactory pain relief for post-Caesarean section pain[7], and this cohort study aims to determine if other NSAIDs may also have the same effect in relieving postCaesarean section pain.

NSAIDs are more cost effective, have less sedative effects and produces less side effects such as emesis[22] compared to narcotic agents. Patients who receive NSAIDs also have fewer concerns over dependency and drug seeking behavior[21] which may be an issue when patients are administered opioids such as Tramadol. Opioids provide superior pain relief in terms of central pain but its use may be limited by patient concerns over dependency as well as the high incidence of side effects associated with its use. The sedative effects of opioids also impair patient recovery and delay the initiation of breastfeeding therefore it is pertinent to find out if NSAIDs can produce
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similar or more efficacious analgesia in post-Caesarean pain compared to opioids in order to reduce the use of opioids in post-Caesarean women.

Finally it is hoped that the outcomes of this cohort study can benefit healthcare practitioners and new mothers in choosing a more suitable and effective oral pain management regimen for women after Caesarean section that will provide optimum pain relief as well as allow new mothers to begin initiating lactation sooner.

1.4 Literature Review 1.4.1 Need for improved pain-management regimen A survey carried out by Karamnlioglu et al in 2003 reported that almost 80% of patients experienced acute pain and received inadequate pain management after abdominal hysterectomy[23]. This result suggests that the regimen for management of pain that is currently employed is still not sufficiently able to alleviate pain especially in post-surgical settings, and can still be improved in order to provide patient comfort and satisfaction as well as facilitate early recovery in post-surgical patients.
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The Agency for Health Care Policy and Research (AHCPR), U.S. Department of Health and Human Services, issued guidelines in 1992 concerning, Acute Pain Management: Operative or Medical Procedures and Trauma. In the guidelines, it is recognized that pain management practices currently adopted in hospitals are still generally inadequate. The AHCPR also noted that post-operative pain that is not managed properly contributes to longer recovery periods as well as reduced patient comfort and higher costs of healthcare[24]. Different pain-management protocols should be looked into to address these problems to benefit both the patient and the healthcare institutions.

Pan PH, in the International Journal of Obstetric Anaesthesia in 2006 stated that proper pain management reduces the need for supplemental analgesia 24-hours post surgery and reduces the risks for complications post-surgery such as the development of chronic pain[3]. Women undergoing surgical births (Caesarean section) should receive efficient pain management to be able to recover quickly from surgery and to initiate early breastfeeding.

1.4.2 Pain management in post-surgical setting. In 2000, Jakobi et al carried out a three month study on 199 women who underwent Caesarean section. The women were divided into two groups, who both received an NSAID and an opioid, but with differing regimens. The results of the study showed that oral analgesia following Caesarean-section provides satisfactory pain relief, is
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easily administered, and is more cost effective compared to the current treatment modalities used for management of pain. The results also showed that post-Caesarean section women whose pain has been effectively managed were able to recover earlier from surgery[7].

In a 2005 review on analgesics used in post-Caesarean pain, Gadsden found that effective post-Caesarean section pain management showed improved mobility and enabled the mother to optimally care for her infant in the immediate post-partum period[6]. Gadsden also found that pain can impair a mother’s ability to breastfeed effectively especially in the post-partum period[6]. This clearly shows the benefits of managing pain effectively especially in new mothers who undergo Caesarean deliveries. In a review published in the International Journal of Obstetric Anaesthesia in 2006, Pan PH et al concluded that proper pain management reduces the need for supplemental analgesia and reduces the risk for post-surgical complications. Pan PH further stated that proper pain management in post-Caaesarean women is required to reduce the risk for thromboembolic events, which may also be precipitated by immobility from inadequate pain control[3]. Apart from that, it is imperative that new mothers receive adequate pain-relief in the post-partum period to allow them to be alert and energetic enough to care for, interact with and breastfeed their newborn infant[3].

1.4.3 Pain management in Initiation of Lactation

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Gadsden et al in 2005 stated that pain and anxiety that were not addressed and treated properly may reduce the ability of new mothers to breastfeed effectively in the immediate post-partum period[6]. It is therefore clear that there is a need for effective pain-management in the post-partum period especially in women undergoing Caesarean births to allow them to breastfeed their infants earlier.

Montgomery et al in 2006 stated that proper analgesia and anaesthesia for post-partum women is important in ensuring breastfeeding success[5]. Women who opt for spontaneous vaginal births (SVD) without administration of epidurals had the highest likelihood of early initiation of breastfeeding while women who underwent Caesarean section experienced a higher difficulty in initiating lactation especially if their postoperative pain is not managed adequately[5]. Post-Caesarean pain that is not managed properly may affect the initiation of breastfeeding and may adversely affect breastfeeding outcomes.

In a study carried out on post-Caesarean women in a health clinic in South Africa, Khan et al in 2009 concluded that post-operative analgesia was effective in ensuring that 38.7% of the patients were pain free, 19.4% of the patients were able to achieve early mobilization and enabled early breastfeeding in 16% of the patients[4].

1.4.4 Benefits of Early Initiation of Lactation In 1999 Clemens et al found evidence that showed early initiation of lactation could reduce the incidence if infantile diarrhoea. Out of the 198 infants in rural Egypt who were recruited, 151 infants (76%) began breastfeeding within the first 3 days of life.
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Clemens found that initiation of breastfeeding shortly after delivery benefited the infant in terms of reducing the occurrence of diarrhoea throughout the first 6 months of life (26% lower rate of diarrhoea compared to infants who began breastfeeding later in life)[25]. Initiation of breastfeeding in the immediate post-partum period improved the health of the infants and enhanced the protective effect of breastfeeding against diarrhoea compared to infants who began breastfeeding later. During the first few days after birth, the mother’s body produces colostrum which has immune properties and is responsible for conferring protection against diarrhoea in new-born infants.

Edmond et al in 2006 also found evidence that showed early initiation of lactation could reduce the risk of neonatal mortality. Edmond et al followed up on 10947 babies in rural Ghana. He found that early initiation of breastfeeding (within the first hour) could reduce neonatal mortality by as much as 22%, while initiation of breastfeeding within the first day could reduce neonatal mortality by as much as 16%[26]. These results clearly show the benefits that could be obtained if initiation of lactation began early, most preferable within the first day of birth.

1.4.5 Safety of Celecoxib in Breastfeeding Hale et al in 2004 carried out a study on 2 mothers regarding the transfer of Celecoxib into breastmilk. The 2 mothers had been on Celecoxib for many weeks, and the levels of Celecoxib in maternal plasma were already at steady-state. Milk was pumped from the breast and was analysed to determine the levels of Celecoxib found in maternal milk. Results showed that the relative infant dose of Celecoxib found in maternal milk is very low (0.3% of maternal dose) and the safety profile of Celecoxib is generally
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high[27]. This is further strengthened by the fact that the 2 infants who were breastfed by the women recruited into this study did not show any untoward effects. In 2005, Gardiner carried out a study in New Zealand to quantify infant exposure to Celecoxib through breast milk. Six women were placed on 200mg Celecoxib od. Milk was pumped out of the breast and analysed. The concentrations of Celecoxib found in the breast milk were low (0.2% of maternal dose). Gardiner concluded that given the low transfer of Celecoxib into milk, breastfeeding during routine dosing would pose minimal risk, especially in patients given Celecoxib for short-term use[28].

1.4.6 Analgesic efficacy of Celecoxib Previous research has shown that individual NSAIDs do differ in their analgesic efficacy[16]. Celecoxib is indicated for management of acute pain in adults, but it is currently not being prescribed in local settings for management of post-surgical pain in post-Caesarean women. However, data obtained from the Oxford League Table of Analgesic Efficacy gives us reason to believe that Celecoxib may be more effective in alleviating pain compared to Tramadol due to the difference in the number needed to treat (NNT) between the two drugs.

The difference in analgesic efficacy is represented in the Oxford League Table of Analgesic Efficacy which compares the relative efficacy of numerous NSAIDs and opioids in the management of pain[29]. In this cohort study, Celecoxib 200mg bd and Tramadol 50mg tds are included. According to the Oxford League Table of Analgesic Efficacy, Celecoxib 200mg has a NNT of 3.5, while Tramadol 50mg has a NNT of

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8.3[28]. NNT values for Mefenamic acid are not included in the Oxford League Table of Analgesic Efficacy.

These NNT values correspond to the number of patients needed to treat for one patient to report at least 50% pain relief over 4-6 hours compared with placebo. A drug that has a lower NNT is more effective in alleviating pain compared to a drug with a higher NNT. The table suggests that Celecoxib 200mg provides superior pain relief in patients with moderate to severe pain compared with Tramadol 50mg, as well as providing pain relief without the side effects associated with opioid use. With this in mind, we aim to see if Celecoxib is better at alleviating pain in post-Caesarean settings compared with Tramadol, which is currently administered to women who undergo Caesarean deliveries.

However, it must be noted that the data obtained from the Oxford League Table is based on studies carried out on patients undergoing different surgical procedures as well as experiencing different types of pain due to different causes. It is important for us to realize that a certain drug that is well-suited to one type of pain setting may have a different effect or no effect at all in a different setting. Therefore, the information obtained from the Oxford League Table cannot be used as a specific guide concerning the relative efficacy of analgesics in managing post-Caesarean section pain since the table does not mention the specific indications for the use of the analgesics included[29].

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This means that there still remains a need for further studies to determine which specific analgesic provides superior pain relief in the management of post-Caesarean section pain to allow early initiation of lactation in new mothers.

1.4.7 Different types of analgesics used in post-surgical pain management Opioid analgesics have been shown to provide adequate pain relief in post-surgical settings[7,18] but the number of documented side effects such as pain, pruritus, nausea, vomiting, sedation and respiratory depression can affect the patients recovery [3,14], subsequently limiting their use in post-surgical setting. NSAIDs on the other hand were associated with narcotic sparing effects such as improved respiratory function, reduction in nausea and vomiting, reduced sedation and there is a suggestion that NSAIDs may improve not only the quality but also the speed of recovery[16]. Furthermore, NSAIDs have also been shown to be effective in a wide variety of postoperative pain states, including thoracotomy, major orthopaedic surgery such as hip arthroplasty, upper and lower abdominal surgery and minor outpatient surgery[16].

A randomized control trial carried out by Reuben et al in 2005 showed that COX-2 inhibitors were effective in improving recovery and restoring function to patients after total knee arthroplasty as well as reducing opioids consumption and their related side effects[30]. A randomized, double-blinded placebo-controlled study conducted by Karamnlioglu et al in 2004 also showed that COX-2 inhibitors were effective in reducing opioids consumption in patients after abdominal hysterectomy[23]. In a survey carried out by Warfield et al in 1995 in the United States, 71% of the respondents reported that they would prefer a non-opioid to an opioid analgesic after
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surgery[30]. The survey did not specify the respondent’s concerns regarding the use of opioids for pain management after surgery, but Warfield speculated that respondents may be concerned about the side effects related to opioid use, as well as the risk of opioid dependency. It is therefore pertinent to see if different analgesia such as NSAIDs can work as well as or even better in offering pain relief compared to opioids in order to address these concerns.

1.5 Research Hypothesis Celecoxib allows earlier initiation of lactation compared to Mefenamic acid and Tramadol.

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1.6 Research Objectives The objectives of this research are

To determine if NSAIDs are more effective in allowing earlier initiation of lactation compared to opioids.

To determine if non-selective COX inhibitors (Mefenamic acid) or COX-2 inhibitors (Celecoxib) are more efficacious in allowing earlier initiation of lactation.

2.0 Materials and Methodology 2.1 Subjects and settings This cohort study was conducted at the obstetric wards for a period of 2 months .

All patients who were admitted into the obstetric wards for elective and emergency Caesarean section were recruited for this cohort study. However, an inclusion and
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exclusion criteria was developed so that the targeted group may be specified more clearly and in order to ensure patient safety at all times. Inclusion criteria
• •

Women between the ages of 18-45 Emergency or elective Caesarean section

Exclusion criteria •

Patients diagnosed with gastrointestinal ulcers Patients with allergies to NSAIDs and/or Tramadol Patients with complicated surgeries requiring admission to high dependency unit (HDU) or intensive care unit (ICU)

Patients who develop complications post-surgery or during surgery

Sample size The number of patients to be recruited for this cohort study is 278, based on an estimated population of 1500 women who undergo Caesarean section at the obstetric wards. The number of patients (278) was calculated using Power and Precision V3, which gives us a confidence level of 95% and confidence interval of +/- 5%.

It is therefore proposed that the number of patients required for each group will be 90. Patients on Mefenamic Acid 500mg tds are placed in group A, patients on Celecoxib 200mg bd in group B and patients on Tramadol 50mg tds are placed in group C, the control group.

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However, at the end of 2 months the number of patients recruited was only 165.

Table 1 Expected number of patients for each drug category

Groups Group A Group B

Medication

Number of patients

Mefenamic Acid 500mg tds 90 Celecoxib 200mg bd 90 90

Group C – Control group Tramadol 50mg tds

2.2 Methodology 2.2.1 Subject preparation Women who underwent Caesarean deliveries were recruited for this cohort study. Where possible, patient consent was taken before patients underwent surgery. This group of patients typically comprised of women who opted for elective Caesarean sections and were admitted into the ward the day before elective Caesarean delivery. However, consent before surgery was not able to be obtained from patients who underwent emergency Caesarean section. In these cases, consent was obtained once the patient returned to the ward after surgery, but before administration of oral analgesia.
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All of the patients recruited for this cohort study received complete explanations of the study, including the importance of the study, its benefits to the patient and future patients, as well as any risks they may face during the study. Patients were also encouraged to voice out any concerns or questions regarding the cohort study. Each of the patients also gave written consent to the researchers after receiving information about the cohort study.

Post-surgery, patients are placed on oral pain medications as indicated by their doctor. The researchers were not involved in determining the type of medication a patient was given. Patients who were given Mefenamic acid 500mg tds, Celecoxib 200mg bd or Tramadol 50mg tds were included in this study.

Patients were served oral medications within 12 hours post-surgery and continued receiving medication until they were discharged from the hospital, which is usually on the 2nd day post-surgery. Patients will also be concurrently placed on parenteral analgesia (IM pethidine), which is administered to the patient every 6-hourly for the first 24 hours post surgery, as per current hospital department policy for post-operative patients (1-2mg/kg of body weight). On day 2, IM pethidine is stopped, and patients will only receive oral pain medication. Patients may request for additional analgesia if necessary. Patient’s request for additional analgesia will be noted down, and the number of times they request for analgesia will also be noted down.

2.2.2 Data collection and interview of patients
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Patient data such as age, race, type of surgery (elective or emergency procedures) and duration of surgery is recorded. The researcher will also record the type of oral analgesia received and time of first administration of analgesia (for example, 3 hours post-surgery). Patients’ request for extra analgesia will also be noted down, if any.

After oral medication is served, the patient will be interviewed regarding the time taken for the patient to first initiate unassisted lactation. The first initiation of unassisted lactation is defined as “the baby suckling at the breast directly for the first time after birth, supported only by the mother and without assistance”.

The time to first initiate unassisted lactation is obtained through patient self-reporting to the researcher. The time will be recorded in hours. The patient will also be questioned on any problems faced during lactation, for example poor milk production, inability to hold the infant in the right position, breast engorgement, plugged milk duct etc.

2.3 Analytic strategies All the data collected were transcribed into the SPSS version 17 software programme. Basic descriptive statistics were used to outline the demographic variables. In simple two-group comparisons, the Student t-test was used to determine the association between dependent and independent demographic variable. When parametric assumptions were not fulfilled, Mann-Whitney test was used for simple two-group comparisons.
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For three-way comparisons between dependent and indepenedent demographic variables, analysis of variance (ANOVA) (or Kruskal-Wallis test is used, when parametric assumptions were not fulfilled). The level of significance, α is set at 0.05 (α=0.05) 3.0 Results 3.1 Demographic data of subjects In the 2 months cohort study, 165 women undergoing Caesarean delivery were recruited, ranging from 20 years of age to 40. 98 of the subjects were Malay, 24 were Chinese, 34 were Indian, and 9 of the subjects were foreigners. 69 patients received Mefenamic Acid 500 tds, 23 patients received Celecoxib 200mg bd and 73 patients received Tramadol 50mg tds.

Figure 4: Total number of subjects recruited according to race

Of the 165 women recruited, only 121 subjects were able to give information regarding time of first initiation of unassisted lactation. 44 subjects were not included in this study as they were not able to give information applicable for this cohort study. 41 subjects had their infant admitted into the ICU, while a further 3 infants passed away during delivery or after delivery, therefore they were excluded from this cohort study.

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Out of the 121 subjects included in the study, 50 subjects were served Mefenamic acid, 19 were served Celecoxib and 52 were given Tramadol.

Figure 5: Distribution of patients based on medication given

3.2 Descriptive data
Table 2: Descriptive data of time to initiate unassisted lactation

Time to initiate lactation (Hours) Mean Median Mode Minimum Maximum 16.17 17.00 18 0 48

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Figure 6 Graph of distribution of number of hours taken to initiate unassisted lactation postsurgery

The mean time to initiate lactation is 16.17 hours, while the median time to initiate lactation is 17.00 hours.

3.3 Difference in the time taken to initiate unassisted lactation between NSAIDs and Tramadol. The mean time taken initiate lactation is shorter in patients who receive Tramadol (M=15.69) compared to NSAIDs (M=16.54).

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A test of normality is carried out using Kolmogorov-Smirnov test. The p-value for Tramadol is 0.02, which is lower than 0.05, therefore the data obtained for this study is not normally distributed.

Kolmogorov-Smirnova DrugType BreastFeed Mefenamic Acid Celecoxib Tramadol Statistic df .139 .113 .161 50 19 52 Sig. .018 .200* .002

Shapiro-Wilk Statistic .960 .959 .901 df 50 19 52 Sig. .091 .562 .000

Table 3: Kolmogorov-Smirnov test of normality.

Since the data is not normally distributed, we cannot use parametric tests such as t-test, therefore to test if this difference in time taken to initiate lactation is significant a nonparametric Mann-Whitney test is carried out.
Table 4: Mann Whitney test on time to initiate lactation between NSAIDs and Tramadol.

BreastFeed Mann-Whitney U Wilcoxon W Z Asymp. Sig. (2-tailed) 1633.000 3011.000 -.844 .399

The null hypothesis (H0) for the Mann-Whitney test is there is no difference in the time taken by mothers to first initiate unassisted lactation between NSAIDS and Tramadol, while the alternate hypothesis (H1) is there is a significant difference in the time taken by mothers to first initiate unassisted lactation between NSAIDS and Tramadol.

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The results of the Mann-Whitney test returned a p-value of 0.399, which is greater than the level of significance of 0.05. The results suggest that there is statistically no significant difference between the time to initiate lactation between NSAIDs and Tramadol. (z = -0.844, p = 0.399).

3.4 Difference in the time taken to initiate unassisted lactation between Mefenamic acid, Celecoxib and Tramadol. The time taken to first initiate unassisted lactation for patients on Mefenamic acid was 16.82 hours, Celecoxib was 15.79 hours and Tramadol was 15.69 hours.

The data obtained is not normally distributed; therefore statistical analysis such as oneway analysis of variance (ANOVA) cannot be used. Instead, Kruskal-Wallis test was carried out to test if there is a significant difference in the number of hours taken by mothers to first initiate unassisted lactation between Mefenamic acid, Celecoxib and Tramadol.

The null hypothesis (H0) is there is no significant difference in the time taken for mothers to first initiate unassisted lactation between Mefenamic acid, Celecoxib and
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Tramadol. The alternate hypothesis (H1) is there is a significant difference in the time taken for mothers to first initiate unassisted lactation between Mefenamic acid, Celecoxib and Tramadol.

Table 5: Kruskal-Wallis test result of time taken to first initiate lactation between Mefenamic acid, Celecoxib and Tramadol.

BreastFeed Chi-Square df Asymp. Sig. .812 2 .666

The probability of the Kruskal-Wallis statistic is 0.666, which is greater than the level of significance of 0.05. We fail to reject the null hypothesis and conclude that the Kruskal-Wallis statistic failed to show a difference in the time taken by mothers to first initiate lactation between Mefenamic acid, Celecoxib and Tramadol (p = 0.666)

3.5 Difference in the time taken to initiate unassisted lactation between races The mean time taken to first initiate unassisted lactation in Malay women was 15.49 hours, in Chinese women 17.07 hours, 17.93 hours in Indian women and 14.50 hours in women of other races.

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Since the data obtained is not normally distributed, a Kruskal-Wallis test was carried out to see if there is a difference in the time taken to initiate unassisted lactation between the three different races.

Table 6: Mean time to initiate lactation in women of different races.

Race Malay Chinese Indian Other Total

Mean 15.49 17.07 17.93 14.50 16.17

N 71 14 28 8 121

Std. Deviation 9.250 10.299 7.468 7.746 8.873

The null hypothesis (H0) of the test is there is no significant difference in the time taken to first initiate unassisted lactation between races while the alternate hypothesis (H1) is there is significant difference in the time taken to first initiate unassisted lactation between races.

The probability of the Kruskal-Wallis test obtained is 0.491, which is greater than the level of significance of 0.05. There is no significant difference in the time taken to first initiate unassisted lactation between mothers of different races (p = 0.491).

Table 7:Kruskal-Wallis test on time to initiate lactation between women of different races.

BreastFeed Chi-Square df Asymp. Sig. 2.412 3 .491
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3.6 Difference in the time taken to initiate unassisted lactation between mothers who undergo elective or emergency Caesarean sections. Women who opted for elective Caesarean deliveries took a mean time of 14.49 hours to first initiate unassisted lactation compared with a mean time of 17.49 hours to first initiate unassisted lactation in women who underwent emergency Caesarean section.

The data obtained is not normally distributed; therefore a non-parametric MannWhitney test is employed to determine if there is significant difference in the time taken to first initiate unassisted lactation between women who underwent elective or emergency Caesarean sections.

The null hypothesis (H0) for the Mann-Whitney test is there is no difference in the time taken by mothers to first initiate unassisted lactation between elective and emergency Caesarean procedures, while the alternate hypothesis (H1) is there is a significant difference in the time taken by mothers to first initiate unassisted lactation between elective and emergency procedures.

The results of the Mann-Whitney test returned a p-value of 0.080, which is greater than the level of significance of 0.05. The results suggest that there is statistically no significant difference between the time to initiate lactation between elective and emergency procedures. (z = -1.753, p = 0.080).
Table 8: Mann-Whitney test on time to initiate lactation between elective and emergency Caesarean procedures.

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BreastFeed Mann-Whitney U Wilcoxon W Z Asymp. Sig. (2-tailed) 1467.000 2898.000 -1.753 .080

4.0 Discussion 4.1 Comparison on time to first initiate unassisted lactation between NSAIDs and Tramadol

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Mothers who experience pain may find it hard to initiate lactation on their own without assistance, because the process of carrying their infant and placing them against the breast to breastfeed requires effort and strength. Mothers whose postoperative pain is not managed properly may not be strong enough to be able to lift their infant to breastfeed them on their own. It is therefore significant to interview the mothers regarding their ability to breastfeed their infant on their own and when they are able to first begin initiation of lactation as we can correlate the results with the effectiveness of the analgesia in managing their pain.

The results of the statistical analysis indicate that there is no difference in the number of hours taken to first initiate unassisted lactation between all three drug types, as well as between drug classes. This means that mothers first began breastfeeding their infant on their own at around the same time between the two drug classes, therefore we infer that there is no significant difference in the efficacy of NSAIDs or Tramadol in producing analgesia in post-Caesarean section women.

The use of opioids typically produce more sedative effects in new mothers, and can lead to delayed initiation of breastfeeding as well as inhibiting effective breastfeeding. However, results of this study showed no difference in time taken to first initiate unassisted lactation in mothers who received oral opioids and mothers who received non-opioid analgesics (Mefenamic acid and Celecoxib).

The results of this cohort study was in accordance with Chang et al in 2005, who found no difference in initiation of breastfeeding between two groups of mothers, one
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who received epidural opioid analgesia and another group which did not receive epidural analgesia[31]

4.2 Comparison on time to first initiate unassisted lactation between Mefenamic acid, Celecoxib and Tramadol Kruskal-Wallis statistics showed no difference in the time taken to first initiate unassisted lactation between Mefenamic acid, Celecoxib and Tramadol. Different analgesics did not significantly improve the time taken for mothers to first begin breastfeeding their infants on their own. The difference in the time taken to initiate lactation is minimal, and may not warrant the need for hospital protocol to be amended to include Celecoxib.

No previous studies have been conducted regarding pain management strategies in post-Caesarean women and the effect of different strategies on initiation of unassisted lactation in the immediate post-partum period. 4.3 Comparison on time to first initiate unassisted lactation between women of different races. In a study conducted by Sheffield et al in 1999, different races perceived pain differently. Specifically, African Americans were more sensitive to pain, which shows that ethnic differences may play a part in perception of pain.

The women recruited for this cohort study comprised of Malays, Chinese, Indians and a small group of foreign women who were categorized as ‘Other’ races. In a study
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conducted by Tan et al in 2008 on 1034 women who underwent elective lower Caesarean section (LSCS), it was found that ethnic Indian patients reported higher pain and used more morphine compared to Chinese or Malays[32]. This difference in perception of pain between different races could affect the time to initiate unassisted lactation, since the Academy of Breastfeeding Medicine Clinical Protocol #15: Analgesia and Anesthesia for the Breastfeeding Mother clearly states that post-partum pain that is not adequately managed leads to an increased risk of post-partum depression as well as poor psychological outcomes that leads to a negative effect on breastfeeding[5].

In this cohort study however, results of the Kruskal-Wallis test on difference in time to first initiate unassisted lactation between races did not reveal any significant findings. There is no significant difference in the time taken to first initiate unassisted lactation between mothers of different races (p = 0.491), which we can interpret as all postCaesarean women received adequate analgesia after delivery or that there were no significant difference in the perception of pain between women of different races.

4.4 Comparison on time to first initiate unassisted lactation between women who undergo elective and emergency Caesarean-section. Women undergoing elective and emergency Caesarean section experience different complications post-surgery. Women who undergo emergency Caesarean section typically have complicated births which can lead to stress both during and after the surgery. A study carried out by Ryding et al in 1997 concluded that 19 out of 25 women (76% of subjects) experienced emergency Caesarean section as a traumatic
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event, and 13 out of the women experienced various forms of post-traumatic stress reactions[33]. Women who experience stress post-surgery will not be psychologically and mentally prepared for breastfeeding, which can lead to problems in initiation of unassisted lactation in new mothers.

Apart from that, a study carried out by Hillan et al in 1995 found that women who underwent emergency Caesarean section experienced a higher occurrence of postoperative morbidity assocated with Caesarean section compared to women who opted for elective Caesarean section[34]. In a prospective study carried out by Nielsen et al in 1984 on 1319 women, he found that the rate of complications associated with emergency Caesarean section was 18.9% compared to only 4.2% for elective Caesarean sections[35]. Women with complicated surgeries may experience higher pain levels and experience longer recovery duration. These factors could affect the time to first initiate unassisted lactation. It is therefore pertinent to see if initiation of lactation could be affected by type of surgical procedure undertaken during Caesarean section (either elective or emergency Caesarean).

The results of statistical analysis showed no significant difference between the time to initiate lactation between women undergoing elective and emergency procedures. Women undergoing Caesarean section in this cohort study began to first initiate unassisted lactation at around the same time regardless of type of surgical procedure performed, either emergency or elective Caesarean section.

4.5 Perceptions of pain in different individuals
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The difference in perception of pain between each individual is of particular importance in this cohort study as it can affect the result outcomes in terms of time taken to first initiate unassisted lactation. If a patient perceives post-Caesarean delivery pain as minimal it is highly likely that the patient will be able to regain strength and function sooner and be able to recover earlier. Patients who have a low tolerance to pain and have a high perception of post-Caesarean delivery pain will not be able to fully regain function and recover as quickly, which may then delay the time taken to first initiate unassisted lactation post-surgery.

Patients who have a higher perception of post-Caesarean delivery pain may require and receive additional analgesia which could affect patient function as well as lead to a higher occurrence of side effects compared to patients who do not request or receive additional analgesia. The side effects associated with the extra analgesia could affect breastfeeding outcomes in terms of time taken to first initiate unassisted lactation.

Differences in perception of pain can be influenced by social background, emotional well-being, age, race, gender, culture, religion as well as past experience[9-11]. It also must be noted that pain in ambulatory and resting conditions may differ, as was reported by several subjects involved in this study. Several subjects felt that ambulatory pain was worse compared to pain at rest, and this could be due to the fact that movement and ambulation aggravated the surgical scar, therefore causing more pain to the patients.

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Regardless of the difference in perceptions of pain in difference individuals, it is accepted that patients who undergo surgeries will experience some form of pain. Women who undergo surgical procedures during delivery, for example Caesarean deliveries, will be placed on analgesia to manage the pain both during and after surgery.

4.6 Potential Limitations 4.6.1 Lack of manpower The initial methodology was to serve pain medication to the subjects within 6 hours, but this was not readily adhered to due to lack of manpower and lack of cooperation by the hospital staff. The research methodology was then amended to include patients who were served medication within 12 hours. The long duration before patients were administered oral medication sometimes led to patients already initiating unassisted lactation before medication was served. This is because the number of hours to initiate lactation is calculated from the time the first dose is administered to the patient and not from time the patient returns to the ward after surgery ends.

Apart from that, Celecoxib is a specialist medicine, and is not readily available in the maternal wards. Patients who were placed on Celecoxib needed to have their prescription signed by a specialist, which then had to be filled out at the inpatient pharmacy department prior to the medication being sent to the wards and subsequently served to the patients. This process was lengthy and several patients placed on Celecoxib had to be excluded from this study because they were served medication
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outside of the time-frame specified for this cohort study (more than 12 hours postsurgery).

4.6.2 Sample size At least 278 patients were supposed to be recruited for this cohort study, but the final sample size was only 165, whereby only 121 were included in the study. The possibility of extending the study was not made available, therefore the study had to be concluded with only 121 patients who fit all the criteria necessary for this cohort study.

The lack of subjects can be due to the fact that many patients had limited access to their infants. 44 women who consented to this study had their infants admitted into the ICU, which prevented them from having full access to their infant. This led to the women not being included in the study, as some had their infants placed in ICU until they were discharged. Also, most of the infants who were admitted into ICU were placed in incubators, thereby interfering with the mothers ability to initiate unassisted lactation, as they were not able to carry their infant and cradle them in their arms to breastfeed them.

3 infants whose mothers had consented to this study also passed away due to poor infant health and poor prognosis. The infant deaths were not caused by the protocols in this cohort study, as the medications involved in this cohort study were not
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administered to the patients prior to birth. These three mothers had to be excluded from this cohort study. The small number of subjects given Celecoxib (23 patients out of 165) is also a limiting factor in this cohort study, because the small sample size does not allow us to properly analyse the effects and efficacy of Celecoxib in post-Caesarean setting. The fact that the number of patients in each group (Group A-Mefenamic acid, Group BCelecoxib and Group C-Tramadol) were not equal can be attributed to the fact that this study is a cohort study, and it is difficult to equalize the sample size for each group, since the patients are placed on oral medications based on doctors’ preference. The researchers are not involved in the decision to administer which oral analgesia the patient is to be given.

The small number of patients placed on Celecoxib may also be due to the reluctance of the doctors in the wards to place their patients on Celecoxib due to cost and safety concerns. Also, the prescription for Celecoxib had to be signed by the specialist and sometimes this was not performed in due time which resulted in patients not being given Celecoxib.

Patients also had to be excluded from the study if they did not receive medication in a timely fashion. Several patients did not receive medication promptly (within 12 hours post-surgery) while several patients did receive medication within the 12-hour time frame but their subsequent second or third dose was not given on time or was missed. This caused us to exclude these patients, as the data obtained from them may be inaccurate.
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4.6.3 Data over or underestimated The data on time taken to first initiate unassisted lactation was obtained from the patient through patient self-reporting to the researcher. The researcher was not present at the bedside of the patients at all time to observe and note down the exact time of initiation of unassisted lactation. The data obtained relied on patients memory, which may be fuzzy and inaccurate, and which may be affected by their pain levels as well as physical and emotional well-being post-delivery. Because of this, there is a possibility that the data obtained may be over or underestimated, for instance patients report initiation of unassisted lactation at approximately 4 hours after medication is served but in actuality it may be earlier or later. This will affect the results of the study, and must therefore be considered when carrying out studies that rely on patient selfreporting and memory for data.

4.6.4 Delay in initiation of lactation that could be caused by variables unrelated to pain medication The women who underwent Caesarean section were also concurrently placed on several other medications. This cohort study did not take into consideration other medications or patient’s medical history as well as current medical conditions that could adversely affect the initiation of unassisted lactation. Different medication may cause maternal side effects that could delay the initiation of unassisted lactation or may cause lactational problems such as lack of milk, plugged milk ducts etc. Current medical conditions were also not taken into consideration in terms of its effects on initiation of unassisted lactation.

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4.6.5 Risk of type II error due to small sample size The expected sample size for this cohort study was 278; however at the end of the cohort study, the number of subjects recruited was only 121. The p-value obtained in the statistical test to determine if there is a significant difference in time to initiate lactation between emergency or elective Caesarean section was 0.080. This value is only slightly above the significant value of α=0.05. This shows that there may be a difference in the time to initiate lactation between emeregency or elective Caesarean section, however the limited sample size could lead to a type-II error in which a false null hypothesis is accepted.

In order to ensure type-II errors do not occur, further studies involving a larger sample size can be carried out to determine if there is significant difference in time to initiate unassisted lactation between women who undergo emergency or elective Caesarean section. The results could be beneficial in terms of investigating the causes for this difference as well as methods or precautionary measures that may be taken in order to reduce such discrepancies.

5.0 Conclusion Patients who received Mefenamic acid, Celecoxib and Tramadol began to initiate unassisted lactation at the same time, regardless of race or type of operative procedure. New mothers were able to regain function and recover well for unassisted breastfeeding to commence within the first day.
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The research hypothesis proposed in this cohort study where patients on Celecoxib would initiate unassisted lactation sooner compared to Mefenamic acid and Tramadol was not proved after statistical testing.

Mefenamic acid and Tramadol provided the same analgesic efficacy compared to Celecoxib. The results of this cohort study did not warrant a need to change current hospital protocol of delivering Mefenamic acid or Tramadol as post-Caesarean oral analgesia to new mothers. The results did not show an improved time to initiate lactation in any of the three oral medications.

5.1 Recommendation for future work Further research is needed to assess breastfeeding outcomes in patients who receive both opioid and non-opioid analgesia (multimodal analgesia) which would address both central and peripheral pain mechanisms.

Women who are primiparous (women having their first child) and multiparous (who who have previously given birth) may have different perceptions of pain, which could
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affect the time taken to first initiate unassisted lactation. Further research should be carried out to assess the post-Caesarean outcomes in these two groups of women.

Long-term breastfeeding outcomes should also be assessed in terms of length of breastfeeding, problems in lactation and benefits of lactation in women who receive post-operative analgesia. This can be achieved by extending the duration of the study, which can also allow the researcher to obtain a larger sample size, which will further strengthen the results of the research.

The cost-effectiveness of difference analgesics in pain management should also be assessed in order to assist healthcare practitioners to choose an oral pain management regime that is most cost effective to the healthcare institute as well as patients. The cost-effectiveness of oral analgesics also play a part in the decision-making process of doctors in deciding which oral analgesic to prescribe patients.

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