C o mplem en t ar y an d A l t e r n a t i v e Me d i c i n e fo r G as tropare s i s Linda A. Lee,
MD
a,
*, Jiande Chen,
PhD
b
, Jieyun Yin,
MD
c
KEYWORDS Acupuncture Gastrointestinal motility STW 5 Rikkunshito Marijuana KEY POINTS Complementary and alternative medicine is used by a significant percentage of individuals with chronic gastrointestinal disorders. Acupuncture and electroacupuncture are the modalities that have been most studied with respect to their effect on visceral hypersensitivity, gastric accommodation, and gastric emptying. Herbal formulations, such as STW 5 and Rikkunshito, may help improve some symptoms of functional dyspepsia, but more studies are needed to understand their mechanisms of action and clinical efficacy. No clinical studies have yet been conducted using marijuana or cannabinoids to treat symptoms of gastroparesis, although endocannibinoids have a wide array of effects on gastrointestinal function.
Complementary and alternative medicine (CAM) is used pervasively throughout the world with a prevalence ranging from 5% to 72%.1 Despite widespread patient interest, there is a need for health care providers to learn more about the vast array of specific practices, and to better understand why patients express interest in knowing more about them. Studies suggest that it is uncommon for most patients to abandon conventional therapy for alternative practices. For some patients with gastrointestinal (GI) disorders, CAM therapies may help provide a sense of control over their disease.2 Patients fearing that their questions may not be well received or that their conventional care practitioner is not knowledgeable, sometimes choose not to fully disclose their
a Division of Gastroenterology and Hepatology, Johns Hopkins Integrative Medicine & Digestive Center, Johns Hopkins University School of Medicine, 2360 West Joppa Road, Suite 200, Lutherville, MD 20193, USA; b Clinical Motility Lab, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, A-505, Baltimore, MD 21224, USA; c Veterans Research and Education Foundation, VA Medical Center, 921 NE 13th Street, Oklahoma City, OK 73104, USA * Corresponding author. E-mail address: [email protected]
Gastroenterol Clin N Am 44 (2015) 137–150 http://dx.doi.org/10.1016/j.gtc.2014.11.011 gastro.theclinics.com 0889-8553/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
138
Lee et al
interest or their usage. In the United States, this issue resulted in the National Center for Complementary and Alternative Medicine to launch the “Time to Talk” campaign in 2011 to encourage patients and their providers to openly discuss complementary practices. This article is intended to help those involved in the care of those with gastroparesis understand the modalities most commonly used and discussed by patients with gastroparesis. CAM use by patients with GI disease or symptoms is not uncommon. A multicenter survey of pediatric patients followed in a GI clinic revealed that 40% of parents of pediatric patients with GI disorders use CAM therapies, with the most important predictors being the lack of effectiveness of conventional therapy, school absenteeism, and the adverse effects of allopathic medication.3 In a UK survey, 26% of patients with GI symptoms sought CAM therapy.4 A survey at a single UK academic center showed the incidence of CAM use was 49.5% for inflammatory bowel disease, 50.9% for irritable bowel syndrome, 20% for general GI diseases, and 27% for controls.5 Studies reporting CAM use by patients with functional bowel disorders have centered primarily on those with irritable bowel syndrome. Relatively few studies exist describing the prevalence of CAM use by those with functional dyspepsia or gastroparesis. In the National Institutes of Health’s Clinical Gastroparesis Research Center’s registry of more than 600 patients, 22% reported using a CAM therapy at the time of initial enrollment (Lee 2014, unpublished data). Gastroparetic patients who used CAM were more likely to be women, white, college-educated, and nonsmokers. The therapies most commonly used by those in the registry were vitamins, herbal supplements, acupuncture, probiotics, and therapeutic massage (Lee 2014, unpublished data). Several of these therapies are reviewed here with respect to gastroparesis, their proposed mechanisms of action, and results from clinical trials. Among various methods of CAM, herbal medicine and acupuncture/electroacupuncture (EA) are the only ones that have been applied in animal models of gastroparesis or impaired gastric motility. Compared with herbal medicine, relatively more reports are available in the literature studying the effects and mechanisms of acupuncture/EA on the pathophysiology of gastroparesis. In addition, a discussion of marijuana and cannabinoids also is included because of the general interest expressed by patients and family members and possible relevance to clinical care. ACUPUNCTURE/ELECTROACUPUNCTURE
Acupuncture/EA affects impaired gastric accommodation, visceral hypersensitivity, and gastric dysmotility (gastric dysrhythmia, antral hypomotility, and delayed gastric emptying). Electroacupuncture and Gastric Accommodation
When food enters the stomach, the proximal stomach relaxes during eating to accommodate the ingested food without producing a large increase in gastric pressure; this reflex is called gastric accommodation. Impaired gastric accommodation is commonly seen in patients with functional dyspepsia and gastroparesis.6 Clinically, it is difficult to treat impaired gastric accommodation in patients with gastroparesis or functional dyspepsia due to coexisting condition of antral hypomotility. Treatment of impaired accommodation with muscle relaxants or adrenergic agents would worsen antral hypomotility. On the other hand, treatment of antral hypomotility often worsens impaired gastric accommodation. In a rodent model of diabetic gastroparesis (1-time injection of streptozotocin), EA at ST36 improved gastric accommodation and the effect was blocked by
Alternative Medicine for Gastroparesis
naloxone.7 In dogs, the same method of EA restored vagotomy-induced impairment in gastric accommodation but showed no effects on gastric accommodation in normal animals (Fig. 1).8 In a recent clinical study, transcutaneous EA (electrical stimulation performed via electrodes placed on the acupuncture points) increased gastric accommodation in patients with functional dyspepsia, assessed by a nutrient drink test.9 Electroacupuncture and Gastric Slow Waves
The gastric slow wave originates in the proximal stomach and propagates distally toward the pylorus. It determines the maximum frequency and propagation direction of gastric contractions. The gastric slow wave has a low frequency of 3 cycles per minute (cpm) in humans, and 5 cpm in dogs and rats. Dysrhythmia in gastric slow waves has been linked to impaired gastric motility, such as antral hypomotility and delayed gastric emptying.10 The effects of EA on gastric slow waves in patients with gastric motility disorders have been widely studied due to the availability of the noninvasive method of electrogastrography. Both EA and needleless transcutaneous EA have been consistently and robustly shown to improve gastric dysrhythmia.11 In diabetic rats, acute EA increased the percentage of normal slow waves from 55% to 69%, and the effect was blocked by naloxone.7 In dogs, EA at ST36 was reported to reduce gastric dysrhythmia induced by duodenal distention8 or rectal distention,12 and the ameliorating effect was mediated via the opioid and vagal pathways. In a rodent study, the effect of EA on gastric slow waves was reported to be site-specific: EA at PC6 showed an inhibitory effect on gastric slow waves, whereas EA at ST36 enhanced gastric slow waves.13 In rats with thermal injury, EA at ST36 improved gastric slow waves with a concurrent suppression of inflammatory cytokine, interleukin-6.14 Electroacupuncture and Gastric Contractions
Coordinated and distally propagated gastric contractions or peristalsis is needed to empty the stomach. Effects and mechanisms of acupuncture/EA on gastric contractions have been investigated in several species, including rats,15–17 rabbits18 and dogs.8,12 500 450
Gastric volume (mL)
400 350 300 250 200
Normal
150
Vagotomized
100
Normal + EA Vagotomized + EA
50 0 -30
-20
-10
0
10
20
Time after meal (min)
Fig. 1. Effects of EA on gastric accommodation in dogs.
30
40
50
60
139
140
Lee et al
In anesthetized rats, antral contractions were enhanced with acupuncturelike stimulation in the limbs but inhibited with similar stimulation in the abdomen or lower chest region16; the excitatory effect was mediated via the vagal pathway, whereas the inhibitory effect was through the activation of sympathetic activity.19 In an in vitro study with diabetic rats, EA at ST36 at both low and high frequencies increased contractility of muscle strips from the gastric antrum and the effect was noted to involve the stem cell factor/c-kit pathway.12 In an in vivo study with the measurement of gastric contractions using strain gauge, EA at ST36 was reported to exert dual effects: enhancement of gastric contractions in rats with hypomotility and inhibition of contractions in rats with hypermotility.17 In dogs, EA at ST36 improved antral hypomotility induced with rectal distention.12 Regular antral contractions were measured by a manometric catheter placed in the antrum via a chronically implanted cannula in the middle of the stomach (Fig. 2A). Rectal distention substantially inhibited postprandial antral contractions (see Fig. 2B) and the effect was reversed by guanethidine (see Fig. 2C), suggesting a sympathetic mechanism. EA at ST36 dramatically enhanced antral contractions during rectal distention (see Fig. 2D) and the effect was abolished by naloxone (see Fig. 2E), suggesting an opioid mechanism. Electroacupuncture and Gastric Emptying
With appropriate selection of acupoints and stimulation parameters, the prokinetic effect of EA on gastric emptying has been consistent and robust in both humans and animals8,15,20–22 ST36 is the most commonly used acupoint for improving gastric emptying and other components of gastric motility, such antral contractions and gastric slow waves. The stimulation frequency ranges from 4 Hz to 100 Hz, with the frequencies of 20 to 40 Hz being the most prevalent. The pulse width is typically set at 0.3 to 0.5 ms, although some studies failed to mention this important parameter. The stimulation amplitude is chosen at a level tolerable by the animals, ranging from 1 to 10 mA, depending on preparation.
Fig. 2. Effects of EA on antral contractions in the postprandial state. (A) No intervention; (B) rectal distention (RD) was applied; (C) rectal distention in the presence of guanethidine; (D) EA at ST36 was applied during RD; (E) EA applied in the presence of naloxone.
Alternative Medicine for Gastroparesis
Gastric emptying was accelerated with EA in normal rats,20 rats with restrain stress,15 rats with thermal injury,14 and diabetic rats with gastroparesis.7 EA at both PC6 and ST36 or ST36 alone also accelerated gastric emptying in dogs with delayed gastric emptying induced by duodenal distention8 or rectal distention.23 A typical example showing the effect and mechanism of EA on rectal distention–induced delay in gastric emptying is presented in Fig. 3. The accelerative effect of EA on gastric emptying may be mediated via the vagal and opioid mechanisms evidenced by the assessment of vagal activity based on the spectral analysis of the heart rate variability and the blockage effect of atropine and naloxone.8,23 Other mechanisms also have been implicated. In diabetic rats, the accelerative effect of EA at ST36 was shown to involve the rescue of the damaged networks of interstitial cells of Cajal (ICC), such as inhibition of ICC apoptosis and enhancement of ICC proliferation.24 In rats with thermal injury, the improvement in gastric emptying with EA was noted to involve the inhibition of interleukin-6.14 Other mechanisms reported in the literature include enhancement of blood flow,25 activation of A delta and/or C afferent fiber,26 and involvement of the serotonin pathway.27 Electroacupuncture and Visceral Hypersensitivity
The effects and mechanisms of EA on visceral hypersensitivity have been investigated in various animal models without gastroparesis. Acupuncture and EA have been most successfully applied for the treatment of pain. Therefore, in general, they are believed to exert analgesic effects on visceral pain as well. In rats with neonatal colorectal chemical irritation, EA at ST36 reduced rectal distention–evoked abdominal electromyogram and the expression of 5HT-3 receptors in the colon.28 In rats with visceral hypersensitivity induced by colorectal distention, EA at ST37 and ST25 improved visceral hypersensitivity assessed by the abdominal withdrawal reflexes and reduced P2X2 and P2X3 receptor expressions in the dorsal root ganglion.29 The same method of EA also was reported to reduce the number of mucosal mast cells in the colon and the expressions of corticotropin-releasing hormone in the hypothalamus and substance P and substance P receptors in the colon of rats with irritable bowel syndrome.30 In our own laboratory, in rats with visceral hypersensitivity established by colorectal injection of acetic acid during the neonatal stage, EA at ST36 reduced visceral hyperalgesia and reversed the enhanced excitability of colon dorsal root ganglion neurons.31
Fig. 3. Effects of EA solid gastric emptying in dogs.
a
P
MD
a,
*, Jiande Chen,
PhD
b
, Jieyun Yin,
MD
c
KEYWORDS Acupuncture Gastrointestinal motility STW 5 Rikkunshito Marijuana KEY POINTS Complementary and alternative medicine is used by a significant percentage of individuals with chronic gastrointestinal disorders. Acupuncture and electroacupuncture are the modalities that have been most studied with respect to their effect on visceral hypersensitivity, gastric accommodation, and gastric emptying. Herbal formulations, such as STW 5 and Rikkunshito, may help improve some symptoms of functional dyspepsia, but more studies are needed to understand their mechanisms of action and clinical efficacy. No clinical studies have yet been conducted using marijuana or cannabinoids to treat symptoms of gastroparesis, although endocannibinoids have a wide array of effects on gastrointestinal function.
Complementary and alternative medicine (CAM) is used pervasively throughout the world with a prevalence ranging from 5% to 72%.1 Despite widespread patient interest, there is a need for health care providers to learn more about the vast array of specific practices, and to better understand why patients express interest in knowing more about them. Studies suggest that it is uncommon for most patients to abandon conventional therapy for alternative practices. For some patients with gastrointestinal (GI) disorders, CAM therapies may help provide a sense of control over their disease.2 Patients fearing that their questions may not be well received or that their conventional care practitioner is not knowledgeable, sometimes choose not to fully disclose their
a Division of Gastroenterology and Hepatology, Johns Hopkins Integrative Medicine & Digestive Center, Johns Hopkins University School of Medicine, 2360 West Joppa Road, Suite 200, Lutherville, MD 20193, USA; b Clinical Motility Lab, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 4940 Eastern Avenue, A-505, Baltimore, MD 21224, USA; c Veterans Research and Education Foundation, VA Medical Center, 921 NE 13th Street, Oklahoma City, OK 73104, USA * Corresponding author. E-mail address: [email protected]
Gastroenterol Clin N Am 44 (2015) 137–150 http://dx.doi.org/10.1016/j.gtc.2014.11.011 gastro.theclinics.com 0889-8553/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
138
Lee et al
interest or their usage. In the United States, this issue resulted in the National Center for Complementary and Alternative Medicine to launch the “Time to Talk” campaign in 2011 to encourage patients and their providers to openly discuss complementary practices. This article is intended to help those involved in the care of those with gastroparesis understand the modalities most commonly used and discussed by patients with gastroparesis. CAM use by patients with GI disease or symptoms is not uncommon. A multicenter survey of pediatric patients followed in a GI clinic revealed that 40% of parents of pediatric patients with GI disorders use CAM therapies, with the most important predictors being the lack of effectiveness of conventional therapy, school absenteeism, and the adverse effects of allopathic medication.3 In a UK survey, 26% of patients with GI symptoms sought CAM therapy.4 A survey at a single UK academic center showed the incidence of CAM use was 49.5% for inflammatory bowel disease, 50.9% for irritable bowel syndrome, 20% for general GI diseases, and 27% for controls.5 Studies reporting CAM use by patients with functional bowel disorders have centered primarily on those with irritable bowel syndrome. Relatively few studies exist describing the prevalence of CAM use by those with functional dyspepsia or gastroparesis. In the National Institutes of Health’s Clinical Gastroparesis Research Center’s registry of more than 600 patients, 22% reported using a CAM therapy at the time of initial enrollment (Lee 2014, unpublished data). Gastroparetic patients who used CAM were more likely to be women, white, college-educated, and nonsmokers. The therapies most commonly used by those in the registry were vitamins, herbal supplements, acupuncture, probiotics, and therapeutic massage (Lee 2014, unpublished data). Several of these therapies are reviewed here with respect to gastroparesis, their proposed mechanisms of action, and results from clinical trials. Among various methods of CAM, herbal medicine and acupuncture/electroacupuncture (EA) are the only ones that have been applied in animal models of gastroparesis or impaired gastric motility. Compared with herbal medicine, relatively more reports are available in the literature studying the effects and mechanisms of acupuncture/EA on the pathophysiology of gastroparesis. In addition, a discussion of marijuana and cannabinoids also is included because of the general interest expressed by patients and family members and possible relevance to clinical care. ACUPUNCTURE/ELECTROACUPUNCTURE
Acupuncture/EA affects impaired gastric accommodation, visceral hypersensitivity, and gastric dysmotility (gastric dysrhythmia, antral hypomotility, and delayed gastric emptying). Electroacupuncture and Gastric Accommodation
When food enters the stomach, the proximal stomach relaxes during eating to accommodate the ingested food without producing a large increase in gastric pressure; this reflex is called gastric accommodation. Impaired gastric accommodation is commonly seen in patients with functional dyspepsia and gastroparesis.6 Clinically, it is difficult to treat impaired gastric accommodation in patients with gastroparesis or functional dyspepsia due to coexisting condition of antral hypomotility. Treatment of impaired accommodation with muscle relaxants or adrenergic agents would worsen antral hypomotility. On the other hand, treatment of antral hypomotility often worsens impaired gastric accommodation. In a rodent model of diabetic gastroparesis (1-time injection of streptozotocin), EA at ST36 improved gastric accommodation and the effect was blocked by
Alternative Medicine for Gastroparesis
naloxone.7 In dogs, the same method of EA restored vagotomy-induced impairment in gastric accommodation but showed no effects on gastric accommodation in normal animals (Fig. 1).8 In a recent clinical study, transcutaneous EA (electrical stimulation performed via electrodes placed on the acupuncture points) increased gastric accommodation in patients with functional dyspepsia, assessed by a nutrient drink test.9 Electroacupuncture and Gastric Slow Waves
The gastric slow wave originates in the proximal stomach and propagates distally toward the pylorus. It determines the maximum frequency and propagation direction of gastric contractions. The gastric slow wave has a low frequency of 3 cycles per minute (cpm) in humans, and 5 cpm in dogs and rats. Dysrhythmia in gastric slow waves has been linked to impaired gastric motility, such as antral hypomotility and delayed gastric emptying.10 The effects of EA on gastric slow waves in patients with gastric motility disorders have been widely studied due to the availability of the noninvasive method of electrogastrography. Both EA and needleless transcutaneous EA have been consistently and robustly shown to improve gastric dysrhythmia.11 In diabetic rats, acute EA increased the percentage of normal slow waves from 55% to 69%, and the effect was blocked by naloxone.7 In dogs, EA at ST36 was reported to reduce gastric dysrhythmia induced by duodenal distention8 or rectal distention,12 and the ameliorating effect was mediated via the opioid and vagal pathways. In a rodent study, the effect of EA on gastric slow waves was reported to be site-specific: EA at PC6 showed an inhibitory effect on gastric slow waves, whereas EA at ST36 enhanced gastric slow waves.13 In rats with thermal injury, EA at ST36 improved gastric slow waves with a concurrent suppression of inflammatory cytokine, interleukin-6.14 Electroacupuncture and Gastric Contractions
Coordinated and distally propagated gastric contractions or peristalsis is needed to empty the stomach. Effects and mechanisms of acupuncture/EA on gastric contractions have been investigated in several species, including rats,15–17 rabbits18 and dogs.8,12 500 450
Gastric volume (mL)
400 350 300 250 200
Normal
150
Vagotomized
100
Normal + EA Vagotomized + EA
50 0 -30
-20
-10
0
10
20
Time after meal (min)
Fig. 1. Effects of EA on gastric accommodation in dogs.
30
40
50
60
139
140
Lee et al
In anesthetized rats, antral contractions were enhanced with acupuncturelike stimulation in the limbs but inhibited with similar stimulation in the abdomen or lower chest region16; the excitatory effect was mediated via the vagal pathway, whereas the inhibitory effect was through the activation of sympathetic activity.19 In an in vitro study with diabetic rats, EA at ST36 at both low and high frequencies increased contractility of muscle strips from the gastric antrum and the effect was noted to involve the stem cell factor/c-kit pathway.12 In an in vivo study with the measurement of gastric contractions using strain gauge, EA at ST36 was reported to exert dual effects: enhancement of gastric contractions in rats with hypomotility and inhibition of contractions in rats with hypermotility.17 In dogs, EA at ST36 improved antral hypomotility induced with rectal distention.12 Regular antral contractions were measured by a manometric catheter placed in the antrum via a chronically implanted cannula in the middle of the stomach (Fig. 2A). Rectal distention substantially inhibited postprandial antral contractions (see Fig. 2B) and the effect was reversed by guanethidine (see Fig. 2C), suggesting a sympathetic mechanism. EA at ST36 dramatically enhanced antral contractions during rectal distention (see Fig. 2D) and the effect was abolished by naloxone (see Fig. 2E), suggesting an opioid mechanism. Electroacupuncture and Gastric Emptying
With appropriate selection of acupoints and stimulation parameters, the prokinetic effect of EA on gastric emptying has been consistent and robust in both humans and animals8,15,20–22 ST36 is the most commonly used acupoint for improving gastric emptying and other components of gastric motility, such antral contractions and gastric slow waves. The stimulation frequency ranges from 4 Hz to 100 Hz, with the frequencies of 20 to 40 Hz being the most prevalent. The pulse width is typically set at 0.3 to 0.5 ms, although some studies failed to mention this important parameter. The stimulation amplitude is chosen at a level tolerable by the animals, ranging from 1 to 10 mA, depending on preparation.
Fig. 2. Effects of EA on antral contractions in the postprandial state. (A) No intervention; (B) rectal distention (RD) was applied; (C) rectal distention in the presence of guanethidine; (D) EA at ST36 was applied during RD; (E) EA applied in the presence of naloxone.
Alternative Medicine for Gastroparesis
Gastric emptying was accelerated with EA in normal rats,20 rats with restrain stress,15 rats with thermal injury,14 and diabetic rats with gastroparesis.7 EA at both PC6 and ST36 or ST36 alone also accelerated gastric emptying in dogs with delayed gastric emptying induced by duodenal distention8 or rectal distention.23 A typical example showing the effect and mechanism of EA on rectal distention–induced delay in gastric emptying is presented in Fig. 3. The accelerative effect of EA on gastric emptying may be mediated via the vagal and opioid mechanisms evidenced by the assessment of vagal activity based on the spectral analysis of the heart rate variability and the blockage effect of atropine and naloxone.8,23 Other mechanisms also have been implicated. In diabetic rats, the accelerative effect of EA at ST36 was shown to involve the rescue of the damaged networks of interstitial cells of Cajal (ICC), such as inhibition of ICC apoptosis and enhancement of ICC proliferation.24 In rats with thermal injury, the improvement in gastric emptying with EA was noted to involve the inhibition of interleukin-6.14 Other mechanisms reported in the literature include enhancement of blood flow,25 activation of A delta and/or C afferent fiber,26 and involvement of the serotonin pathway.27 Electroacupuncture and Visceral Hypersensitivity
The effects and mechanisms of EA on visceral hypersensitivity have been investigated in various animal models without gastroparesis. Acupuncture and EA have been most successfully applied for the treatment of pain. Therefore, in general, they are believed to exert analgesic effects on visceral pain as well. In rats with neonatal colorectal chemical irritation, EA at ST36 reduced rectal distention–evoked abdominal electromyogram and the expression of 5HT-3 receptors in the colon.28 In rats with visceral hypersensitivity induced by colorectal distention, EA at ST37 and ST25 improved visceral hypersensitivity assessed by the abdominal withdrawal reflexes and reduced P2X2 and P2X3 receptor expressions in the dorsal root ganglion.29 The same method of EA also was reported to reduce the number of mucosal mast cells in the colon and the expressions of corticotropin-releasing hormone in the hypothalamus and substance P and substance P receptors in the colon of rats with irritable bowel syndrome.30 In our own laboratory, in rats with visceral hypersensitivity established by colorectal injection of acetic acid during the neonatal stage, EA at ST36 reduced visceral hyperalgesia and reversed the enhanced excitability of colon dorsal root ganglion neurons.31
Fig. 3. Effects of EA solid gastric emptying in dogs.
a
P
