Drug Combination Improved Local Analgesia After Cesarean

MONTEREY, CALIF. – Two drugs work better than one when it comes to reducing pain and inflammation with local therapy after cesarean delivery, researchers reported.

In a randomized trial of 60 women who used subcutaneous drug delivery, the area under the curve for postoperative pain scores while sitting was roughly 30% less and supplemental opioid requirements were roughly 40% less when the nonsteroidal anti-inflammatory drug ketorolac was added to bupivacaine. Wound exudate levels of the inflammatory markers interleukin-6 and -10 also were lower.

"Giving a low dose peripherally of nonsteroidal ketorolac has both an anti-inflammatory and an analgesic effect," commented lead author Dr. Brendan Carvalho, an anesthesiologist at Lucile Packard Children’s Hospital in Stanford, Calif.

"This suggests that there is a local mediation effect – this is not a systemic effect – and it may give birth to the whole concept of being able to give very small doses directly in the wound," he said at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.

"You could even create a multimodal analgesic protocol with small doses of drugs that will not have the high side effects based on big systemic doses, and they can work exactly in the area that we know is most important for inflammation and pain propagation."

In contrast, there were no significant improvements in study outcomes when subcutaneous hydromorphone was added to bupivacaine. "This probably could have been anticipated if you look at the balance of the literature, looking at the efficacy of opioids and nonsteroidals peripherally administered," Dr. Carvalho said.

Session attendee Dr. David R. Gambling of the Sharp Mary Birch Hospital for Women in San Diego questioned the impact of the catheter used to deliver the drugs. "Do you think that having that foreign body in place affects the release of the mediators you were measuring, and if that’s the case, do you think patient movement and irritation of the foreign body could have had an effect on the result?" he asked.

The point is a good one, Dr. Carvalho acknowledged. However, "to be able to follow someone continuously [without a catheter in place] would require invasive [needle procedures] as well as punch biopsies. ... There’s sort of a long way to go, and maybe the whole idea behind this is to encourage people to think of better ways of doing this."

Dr. Andrea Fuller of the University of Colorado Hospital in Aurora, who also attended the session, said, "I’m wondering clinically how to use this. If you don’t have an ON-Q pump [to deliver the drug], are you doing things like asking your obstetricians to put some ketorolac in infiltrate right at the site, or even putting it in a TAP [transversus abdominus plane] block – it might be close enough."

"It’s way too early to say," Dr. Carvalho replied. "I am not recommending the use [of a nonsteroidal agent peripherally] yet, until we truly understand what these drugs are doing. ... It’s a growing area, and I think a few years from now, a lot of the drug administration will be where it should be as opposed to systemically."

The trial participants were 60 healthy women with term singleton pregnancies who underwent elective cesarean delivery with spinal anesthesia. The investigators placed elastomeric ON-Q pumps subcutaneously in the incisional wound to permit collection of wound exudate and instillation of agents.

The women were randomized equally into three groups given continuous subcutaneous instillation for 48 hours after surgery of bupivacaine at 10 mg/hr only (as an active control); bupivacaine plus ketorolac at 0.6 mg/hr; or bupivacaine plus hydromorphone at 0.04 mg/hr.

The drugs were intentionally "given in very small doses, which we believe would not be systemically effective, so it’s not a systemic absorption effect," Dr. Carvalho noted.

Pain intensity was measured at 4, 24, and 48 hours post surgery, both at rest and during activity, using the verbal pain scale, on which values range from 0 to 10. Wound exudate was collected at the same time points and assayed for a wide variety of cytokines.

On average, the women were about 32 years old and had a parity of 1. Eighty percent had had a previous cesarean delivery.

Trial results showed that the area under the curve for postoperative pain scores while sitting was approximately 250 for women given bupivacaine only, versus 175 for women given bupivacaine plus ketorolac (P = .018), Dr. Carvalho reported. There were no significant differences in pain scores while at rest.

Compared with bupivacaine alone, bupivacaine plus ketorolac was associated with lower levels of interleukin-6 (P = .012) and interleukin-10 (P = .004) in wound exudate.

Postoperative supplemental opioid analgesic use was approximately 25 mg of morphine equivalents for women in the bupivacaine-ketorolac group, compared with 40 mg for their counterparts in the bupivacaine-only group (P = .020).

None of the women had significant adverse events or study-related complications, and there were no hematomas, infections, or delays in wound healing. One woman developed a subincisional fluid collection.

"The majority of patients we enrolled had had previous cesarean deliveries, which may [have introduced] bias, as patients having second C-sections may respond differently from someone who is undergoing a cesarean for the first time," Dr. Carvalho acknowledged. Additionally, there was some "empiric guessing" involved in the selection of drug doses, and the study focused only on the acute inflammatory period.

"The next plan is to compare systemic versus peripheral administration of various other drugs, and to start understanding the mechanisms behind what is happening in the periphery," he concluded. "We have a very delicate balance where if we inhibit inflammation too much, then we have delayed wound healing. If we accelerate it too much, we might get hypertrophic scarring. So it’s a delicate balance that we can intervene on and maybe improve analgesia, but we mustn’t affect the balance of wound healing."

Dr. Carvalho disclosed that he has a relationship with I-Flow, manufacturer of the pump used in the study.

MONTEREY, CALIF. – Two drugs work better than one when it comes to reducing pain and inflammation with local therapy after cesarean delivery, researchers reported.

In a randomized trial of 60 women who used subcutaneous drug delivery, the area under the curve for postoperative pain scores while sitting was roughly 30% less and supplemental opioid requirements were roughly 40% less when the nonsteroidal anti-inflammatory drug ketorolac was added to bupivacaine. Wound exudate levels of the inflammatory markers interleukin-6 and -10 also were lower.

"Giving a low dose peripherally of nonsteroidal ketorolac has both an anti-inflammatory and an analgesic effect," commented lead author Dr. Brendan Carvalho, an anesthesiologist at Lucile Packard Children’s Hospital in Stanford, Calif.

"This suggests that there is a local mediation effect – this is not a systemic effect – and it may give birth to the whole concept of being able to give very small doses directly in the wound," he said at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.

"You could even create a multimodal analgesic protocol with small doses of drugs that will not have the high side effects based on big systemic doses, and they can work exactly in the area that we know is most important for inflammation and pain propagation."

In contrast, there were no significant improvements in study outcomes when subcutaneous hydromorphone was added to bupivacaine. "This probably could have been anticipated if you look at the balance of the literature, looking at the efficacy of opioids and nonsteroidals peripherally administered," Dr. Carvalho said.

Session attendee Dr. David R. Gambling of the Sharp Mary Birch Hospital for Women in San Diego questioned the impact of the catheter used to deliver the drugs. "Do you think that having that foreign body in place affects the release of the mediators you were measuring, and if that’s the case, do you think patient movement and irritation of the foreign body could have had an effect on the result?" he asked.

The point is a good one, Dr. Carvalho acknowledged. However, "to be able to follow someone continuously [without a catheter in place] would require invasive [needle procedures] as well as punch biopsies. ... There’s sort of a long way to go, and maybe the whole idea behind this is to encourage people to think of better ways of doing this."

Dr. Andrea Fuller of the University of Colorado Hospital in Aurora, who also attended the session, said, "I’m wondering clinically how to use this. If you don’t have an ON-Q pump [to deliver the drug], are you doing things like asking your obstetricians to put some ketorolac in infiltrate right at the site, or even putting it in a TAP [transversus abdominus plane] block – it might be close enough."

"It’s way too early to say," Dr. Carvalho replied. "I am not recommending the use [of a nonsteroidal agent peripherally] yet, until we truly understand what these drugs are doing. ... It’s a growing area, and I think a few years from now, a lot of the drug administration will be where it should be as opposed to systemically."

The trial participants were 60 healthy women with term singleton pregnancies who underwent elective cesarean delivery with spinal anesthesia. The investigators placed elastomeric ON-Q pumps subcutaneously in the incisional wound to permit collection of wound exudate and instillation of agents.

The women were randomized equally into three groups given continuous subcutaneous instillation for 48 hours after surgery of bupivacaine at 10 mg/hr only (as an active control); bupivacaine plus ketorolac at 0.6 mg/hr; or bupivacaine plus hydromorphone at 0.04 mg/hr.

The drugs were intentionally "given in very small doses, which we believe would not be systemically effective, so it’s not a systemic absorption effect," Dr. Carvalho noted.

Pain intensity was measured at 4, 24, and 48 hours post surgery, both at rest and during activity, using the verbal pain scale, on which values range from 0 to 10. Wound exudate was collected at the same time points and assayed for a wide variety of cytokines.

On average, the women were about 32 years old and had a parity of 1. Eighty percent had had a previous cesarean delivery.

Trial results showed that the area under the curve for postoperative pain scores while sitting was approximately 250 for women given bupivacaine only, versus 175 for women given bupivacaine plus ketorolac (P = .018), Dr. Carvalho reported. There were no significant differences in pain scores while at rest.

Compared with bupivacaine alone, bupivacaine plus ketorolac was associated with lower levels of interleukin-6 (P = .012) and interleukin-10 (P = .004) in wound exudate.

Postoperative supplemental opioid analgesic use was approximately 25 mg of morphine equivalents for women in the bupivacaine-ketorolac group, compared with 40 mg for their counterparts in the bupivacaine-only group (P = .020).

None of the women had significant adverse events or study-related complications, and there were no hematomas, infections, or delays in wound healing. One woman developed a subincisional fluid collection.

"The majority of patients we enrolled had had previous cesarean deliveries, which may [have introduced] bias, as patients having second C-sections may respond differently from someone who is undergoing a cesarean for the first time," Dr. Carvalho acknowledged. Additionally, there was some "empiric guessing" involved in the selection of drug doses, and the study focused only on the acute inflammatory period.

"The next plan is to compare systemic versus peripheral administration of various other drugs, and to start understanding the mechanisms behind what is happening in the periphery," he concluded. "We have a very delicate balance where if we inhibit inflammation too much, then we have delayed wound healing. If we accelerate it too much, we might get hypertrophic scarring. So it’s a delicate balance that we can intervene on and maybe improve analgesia, but we mustn’t affect the balance of wound healing."

Dr. Carvalho disclosed that he has a relationship with I-Flow, manufacturer of the pump used in the study.

MONTEREY, CALIF. – Two drugs work better than one when it comes to reducing pain and inflammation with local therapy after cesarean delivery, researchers reported.

In a randomized trial of 60 women who used subcutaneous drug delivery, the area under the curve for postoperative pain scores while sitting was roughly 30% less and supplemental opioid requirements were roughly 40% less when the nonsteroidal anti-inflammatory drug ketorolac was added to bupivacaine. Wound exudate levels of the inflammatory markers interleukin-6 and -10 also were lower.

"Giving a low dose peripherally of nonsteroidal ketorolac has both an anti-inflammatory and an analgesic effect," commented lead author Dr. Brendan Carvalho, an anesthesiologist at Lucile Packard Children’s Hospital in Stanford, Calif.

"This suggests that there is a local mediation effect – this is not a systemic effect – and it may give birth to the whole concept of being able to give very small doses directly in the wound," he said at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.

"You could even create a multimodal analgesic protocol with small doses of drugs that will not have the high side effects based on big systemic doses, and they can work exactly in the area that we know is most important for inflammation and pain propagation."

In contrast, there were no significant improvements in study outcomes when subcutaneous hydromorphone was added to bupivacaine. "This probably could have been anticipated if you look at the balance of the literature, looking at the efficacy of opioids and nonsteroidals peripherally administered," Dr. Carvalho said.

Session attendee Dr. David R. Gambling of the Sharp Mary Birch Hospital for Women in San Diego questioned the impact of the catheter used to deliver the drugs. "Do you think that having that foreign body in place affects the release of the mediators you were measuring, and if that’s the case, do you think patient movement and irritation of the foreign body could have had an effect on the result?" he asked.

The point is a good one, Dr. Carvalho acknowledged. However, "to be able to follow someone continuously [without a catheter in place] would require invasive [needle procedures] as well as punch biopsies. ... There’s sort of a long way to go, and maybe the whole idea behind this is to encourage people to think of better ways of doing this."

Dr. Andrea Fuller of the University of Colorado Hospital in Aurora, who also attended the session, said, "I’m wondering clinically how to use this. If you don’t have an ON-Q pump [to deliver the drug], are you doing things like asking your obstetricians to put some ketorolac in infiltrate right at the site, or even putting it in a TAP [transversus abdominus plane] block – it might be close enough."

"It’s way too early to say," Dr. Carvalho replied. "I am not recommending the use [of a nonsteroidal agent peripherally] yet, until we truly understand what these drugs are doing. ... It’s a growing area, and I think a few years from now, a lot of the drug administration will be where it should be as opposed to systemically."

The trial participants were 60 healthy women with term singleton pregnancies who underwent elective cesarean delivery with spinal anesthesia. The investigators placed elastomeric ON-Q pumps subcutaneously in the incisional wound to permit collection of wound exudate and instillation of agents.

The women were randomized equally into three groups given continuous subcutaneous instillation for 48 hours after surgery of bupivacaine at 10 mg/hr only (as an active control); bupivacaine plus ketorolac at 0.6 mg/hr; or bupivacaine plus hydromorphone at 0.04 mg/hr.

The drugs were intentionally "given in very small doses, which we believe would not be systemically effective, so it’s not a systemic absorption effect," Dr. Carvalho noted.

Pain intensity was measured at 4, 24, and 48 hours post surgery, both at rest and during activity, using the verbal pain scale, on which values range from 0 to 10. Wound exudate was collected at the same time points and assayed for a wide variety of cytokines.

On average, the women were about 32 years old and had a parity of 1. Eighty percent had had a previous cesarean delivery.

Trial results showed that the area under the curve for postoperative pain scores while sitting was approximately 250 for women given bupivacaine only, versus 175 for women given bupivacaine plus ketorolac (P = .018), Dr. Carvalho reported. There were no significant differences in pain scores while at rest.

Compared with bupivacaine alone, bupivacaine plus ketorolac was associated with lower levels of interleukin-6 (P = .012) and interleukin-10 (P = .004) in wound exudate.

Postoperative supplemental opioid analgesic use was approximately 25 mg of morphine equivalents for women in the bupivacaine-ketorolac group, compared with 40 mg for their counterparts in the bupivacaine-only group (P = .020).

None of the women had significant adverse events or study-related complications, and there were no hematomas, infections, or delays in wound healing. One woman developed a subincisional fluid collection.

"The majority of patients we enrolled had had previous cesarean deliveries, which may [have introduced] bias, as patients having second C-sections may respond differently from someone who is undergoing a cesarean for the first time," Dr. Carvalho acknowledged. Additionally, there was some "empiric guessing" involved in the selection of drug doses, and the study focused only on the acute inflammatory period.

"The next plan is to compare systemic versus peripheral administration of various other drugs, and to start understanding the mechanisms behind what is happening in the periphery," he concluded. "We have a very delicate balance where if we inhibit inflammation too much, then we have delayed wound healing. If we accelerate it too much, we might get hypertrophic scarring. So it’s a delicate balance that we can intervene on and maybe improve analgesia, but we mustn’t affect the balance of wound healing."

Dr. Carvalho disclosed that he has a relationship with I-Flow, manufacturer of the pump used in the study.