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Kayla Richwine

NTDT401-80
May 8, 2015
Use of Magnesium as a Postoperative Analgesic
Introduction:
Magnesium is an important mineral and the second most abundant
intracellular cation that assists the human body in a variety of ways. 1 Over 300
enzyme systems need magnesium as a cofactor to function. 2 Magnesium is used to
make energy both aerobically and anaerobically. It also has a role in making DNA,
RNA, bone, and the antioxidant glutathione. Magnesium also regulates calcium and
potassium ions as they enter and exit body cells. This function is important to the
regulation of nerve impulse conduction, muscle contraction, and normal heart
rhythm. Such regulatory qualities of magnesium allow it to relax muscles which is
the reason it is found in some antacid and laxative products. Naturally, magnesium
is found in green, leafy vegetables, nuts, and grains. 3 Recent studies on magnesium
have found it to have analgesic effects that can relieve pain after surgery as well as
decrease opioid and other pain-relieving drug intake following surgery. This
knowledge is important to the medical field because pain-reducing drugs are often
consumed by patients following surgical procedures, but they may produce negative
side effects like respiratory depression, nausea, and vomiting or hypotension.
Magnesium may partner with opioids to increase the duration of their effects which
decreases drug intake by the patient. This, in turn, reduces the money spent on
medication as well as the resulting side effects. 4

How Magnesium Inhibits Pain:

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The method by which magnesium inhibits pain is not yet completely
understood. Described most basically, magnesium interferes with calcium channels
and NMDA receptors.4 By one method it partially blocks calcium from entering cells
which inhibits release of the neurotransmitter acetylcholine. Acetylcholine can carry
pain signals, and inhibiting its release will inhibit pain signals being sent to the
brain.1 Magnesium also inhibits pain because it acts as a N-methyl-D-aspartate
(NMDA) receptor antagonist which means it blocks glutamate from attaching at the
NMDA receptor site.5 There are two major neurons in the human body that recognize
pain. They are the C-fiber nociceptors and A-delta nociceptors. Inflammation causes
the nociceptors to fire pain signals spontaneously which results in the sensation of
ongoing pain. Continual discharge of C-fiber nociceptors stimulates glutamate to
bind to spinal NMDA receptors, activating them. NMDA activation sensitizes the
spinal cord neuron, causing it to react more to all of its stimuli, including pain. 6
When glutamate is able to bond to the NMDA receptor, it causes increased pain
sensations and reduced functionality of opioid receptors. Increasing magnesium
levels in the body provides the body with adequate magnesium to bind to spinal
NMDA receptors, thereby preventing glutamate from binding and causing increased
levels of pain. It also allows opioid receptors to function normally which will allow
lower amounts of these drugs to effectively reduce pain. 5

Proof of Magnesiums Analgesic Effects:


A 2014 randomized, double-blind study on forty women undergoing a Total
Abdominal Hysterectomy (TAH) tested the use of magnesium as an analgesic. In this
study, 20 of the patients were given 50 milligrams (mg) per kilogram (kg) of body
weight of magnesium sulfate in a saline solution 15 minutes before they were given

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general anesthesia. The other 20 patients were assigned to the control group and
were given saline solution without the magnesium sulfate. Immediately following
the surgery and at 6, 12, and 24 hours after surgery, patients were asked to rate
their pain on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain
possible. The difference in pain between the two groups immediately following
surgery was not statistically significant. At six hours post-operation, the magnesium
group reported an average pain of 6.45 on the pain scale. The saline group reported
9.80 on the pain scale. At twelve hours post-operation, the magnesium group
reported an average pain of 5.90 on the pain scale, while the saline group reported
a 7.80. At 24 hours post-operation, the magnesium group reported an average pain
of 4.60 on the pain scale with the saline group reporting a 5.90. When requested,
patients in the TAH study were given the drug pethidine as a pain-reliever. The
average consumption of pethidine in the magnesium group was 16.75 mg, while the
average in the saline group was 68.0 mg. No nausea, vomiting, or
hypermagnesemia were reported. In relation to a TAH, the results of this study
clearly support the hypothesis that magnesium decreases pain and opioid intake. 4
A similar study performed in 1996 by Wilder-Smith et al. on patients also
undergoing TAH found that magnesium did not reduce postoperative pain. Twenty
four patients participated in this study in which half of them were given an initial
dose of 200 mg of magnesium levulinate intravenously at the time of anesthesia.
Then, magnesium levulinate intravenous administration continued for five hours at
a rate of 200 mg per hour. This five hour time period spanned from the time of
anesthesia administration through the beginning of the postoperative period. The
other half of the patients were given a placebo by the same process. 7 Taheri et al.
suggest that the results of this study are unreliable due to a small sample size of 24

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participants as well as administration of an inadequate amount of magnesium
required for analgesia in this type of operation. In the study by Taheri et al., patients
were given an initial dose of 50 mg of magnesium per kilogram of body weight. 4 The
average weight of patients in the magnesium group in the study by Wilder-Smith et
al. was 61.7 kg, and each patient was given a maximum of 1200 mg of
magnesium.7 In comparison, a patient weighing 61.7 kg in the study by Taheri et al.
would have been given 3085 mg of magnesium. Therefore, the significantly lower
dosage of magnesium in the study by Wilder-Smith et al. was likely the major cause
of the failure of the study to demonstrate the analgesic effects of magnesium. 4
In another 2014 randomized, double-blind study, the analgesic effects of
magnesium were tested on 100 patients undergoing elective orthopedic surgeries
of elbow, forearm, and hand under supraclavicular brachial plexus block. 1 This
block is a method of injecting local anesthesia in order to anesthetize the upper
limbs.8 In this study, .50% ropivacaine was used as the local anesthetic. This
anesthetic was mixed with 150 mg magnesium sulfate in a saline solution and
administered to 50 of the participants. The other 50 participants were given
ropivacaine and saline. This study tested the duration of the sensory blockade using
pinpricks to see if magnesium prolongs the effects of other analgesics like the
supraclavicular brachial plexus block. The researchers found that the average
duration of the sensory blockade of the magnesium group was 456.21 minutes. The
average duration for the saline group was 289.67 minutes. Nausea occurred in four
patients given magnesium and two patients in the control group, but this difference
is not statistically significant. This study also demonstrated magnesiums ability to
decrease pain-relieving drug intake. The average time until the first request for
pain-relievers post-operation in the magnesium group was 461.71 minutes, while

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the average time for the saline group was 379.79 minutes. Significant differences in
the amount of rescue analgesia required by the two groups were also
demonstrated.1 Rescue analgesia is pain-reducing medicine taken in addition to
regularly scheduled analgesic medications. It is to be taken during episodes of
pain not controlled by a patients scheduled analgesic regimen. 9 The average total
amount of rescue analgesia needed by the magnesium group was 76.82 mg, while
the average amount for the saline group was 104.35 mg. According to the
researchers, the decreased pain and lack of need for prescribed pain-reducing drugs
and rescue analgesia in the magnesium group is due to prolonged duration of
sensory block.1
A 2013 randomized, double-blind study on children also demonstrated
magnesiums analgesic effects. This study included 80 children aged two to six
undergoing inguinal herniorrhaphy. Forty children were given the local anesthetic
ropivacaine (Group R). The other forty children were given ropivacaine mixed with
50 mg of magnesium (Group RM). Pain levels were measured by surveying the child
and parents immediately after surgery as well as at 6, 24, 48, and 72 hours after
surgery. The amount of pain was based on the Parents Postoperative Pain Measure
(PPPM) in which parents recorded their answers to 15 questions in regards to the
childs pain at each of the pre-selected time intervals. The 15 questions can be
answered with yes or no, whereas yes represents one point on the pain scale
and no represents zero points on the pain scale. Up to 15 points are possible using
the PPPM with greater than or equal to six points representing clinically significant
pain. Examples of questions asked on the PPPM are, Does your child complain more
than usual? Look more flushed than usual? Refuse to eat? The difference in pain
between the groups was not significant immediately following surgery. However, the

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pain scores at 6, 24, 48, and 72 hours after surgery according to the PPPM were
significantly lower for those in Group RM. The most significant difference was at six
hours after surgery with Group R reporting a median PPPM score of approximately
4.5 and Group RM reporting a median PPPM score of approximately 2. Both groups
demonstrated similar incidences of agitation and nausea, demonstrating the
increased amount of magnesium did not produce any additional side effects. This
study also reported that the decrease in pain led to a significant decrease in
recovery time. Those in Group RM regained full functional activity at a median of
two days, whereas those in Group R had a median of three days. Ninety percent of
children in Group RM returned to normal activity after 48 hours, whereas it took
nearly 96 hours for 90% the children in Group R to return to normal activity. In this
study, 39.5% of patients in Group R required rescue analgesia, while only 15.4% in
Group RM did. Additionally, the parents were given acetaminophen syrup to take
home and told to give it to their child for pain management every four to six hours
unless the medicine was not required. In Group R, 52.6% of children were given
acetaminophen at home. In Group RM, 20.5% of children were given acetaminophen
at home. The average total quantity of acetaminophen taken in Group R was higher
and statistically significant, and the time until the first dose of any analgesic after
surgery had a median of 390 minutes for Group R as compared to 485 minutes for
Group RM. The prolonged duration until the first dose of pain-reducing drugs was
required exemplifies magnesiums ability to enhance the effects of other analgesics.
This study concluded that, when used along with ropivacaine, magnesium is
effective in reducing pain, rescue analgesia, and pain-relieving drug intake without
producing any of its own, additional side effects. Magnesium also significantly
reduced recovery time.10

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Another study by Birbicer et al. on the use of magnesium in postoperative
pain reduction following inguinal herniorrhaphy in children found that magnesium
did not have an analgesic effect. 11 Once again, this study failure is likely due to
administration of inadequate amounts of analgesia. 10 While both studies used the
same dosage of 50 mg of magnesium sulfate, the study by Birbicer used a lower
amount of ropivacaine which Kim et al. note is not sufficient to provide adequate
analgesia. The study by Birbicer et al. also had shortcomings in its assessment, as
pain was only measured at six hours after surgery. 10, 11 Kim et al. report that
according to the mechanism of action of magnesium and the results of previous
studies, this time period is not sufficient to observe the effects of magnesium as an
adjuvant for caudal analgesia. Kim et al. note that their pain assessment spanned
72 hours and clearly demonstrated the analgesic effects of magnesium from 6 to 72
hours post-operation. These results demonstrate that studies of magnesium as an
analgesic must monitor pain for longer than six hours as the analgesic effects may
not even begin until then.10
A 2013 study on mice given Mg21 chloride, a form of magnesium,
demonstrated a decreased response to pain in comparison to the control group.
Three tests were done to come to this conclusion. In each test, results of the control
group were compared to three groups of mice that had been given 37.5, 75, and
150 mg of Mg21 chloride per kilogram of body weight. The Tail Flick (TF) test
involved exposing the tails of the mice to a heat source and tracking how long it
took until the mice flicked their tails away from the painful heat. Mice given Mg21
chloride prior to the TF test demonstrated a 72.68% reduction in pain. The second
test was the Hot Plate (HP) test. This involved placing mice on a heated surface. The
time until a mouse first demonstrated a behavioral sign of pain, defined as licking a

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hind paw, vocalization, or an escape response, was measured. The HP test found
that Mg21 chloride reduced pain by 31.89%. The third test was the Writhing Test
which measured the number of abdominal stretches by the mice in response to
injection of acetic acid. Abdominal stretches were considered to be responses to
pain. In comparison to the control group, mice that had been given Mg21 chloride
demonstrated an 86.03% reduction in pain at 5 minutes, 89.54% at 20 minutes, and
85.71% at 30 minutes after administration of magnesium. The results from all three
tests demonstrate Mg21 chlorides effectiveness at reducing pain in mice which is
knowledge that can be applied to humans. 12
In a 2010 randomized, double-blind study on 40 patients undergoing total hip
replacement arthroplasty, it was also found that pain can be suppressed by use of
magnesium. Twenty patients were assigned to Group M and were given 50 mg of
magnesium sulfate per kilogram (kg) of body weight intravenously for 15 minutes
after administration of spinal anesthesia. Then, the patients continued to receive 50
mg per kg per hour for the duration of the operation. The other 20 patients were
assigned to Group S and received saline via the same methods. Pain was measured
by patients verbally rating their pain on a scale of 0 to 100 where 0 represents no
pain and 100 represents the worst pain imaginable. Average pain scores between
the two groups were not statistically significant immediately after surgery or 30
minutes later. However, pain scores in the magnesium group were significantly
lower at 4, 24, and 48 hours post-operation. The median pain score for Group M at
four hours post-operation was 30, while Group S reported a median score of 50. At
24 hours after the operation, Group M reported a median pain score of 20, while
Group S reported a median score of 38. At 48 hours post-operation, Group M
reported a median pain score of 12, while Group S reported a median score of 29. 13

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Side effects like shivering, nausea, and vomiting were similar between the
two groups. The average amount of analgesics consumed by the patients in Group
M was significantly lower at 4, 24, and 48 hours post-operation. At 48 hours after
the operation, the patients in Group M had consumed an average of approximately
30 milliliters (ml) of pain-killers while those in Group S consumed an average of
approximately 50 ml. The researchers concluded that I.V. magnesium sulfate
administration during spinal anesthesia improves postoperative analgesia as well
as decreases pain-reducing drug intake after surgery. 13

The Delay of Magnesiums Analgesic Effects:


Magnesiums analgesic effects do not appear immediately. This knowledge
must be taken into consideration by researchers, health professionals, and patients
any time magnesium is administered for the purpose of reducing pain. The study on
patients undergoing a total abdominal hysterectomy (TAH) demonstrated no
significant difference in pain at emergence time between the control group and the
group given magnesium, but did demonstrate differences starting at six hours postoperation.4 The study on children undergoing inguinal herniorrhaphy demonstrated
no significant difference in pain during the first 180 minutes post-operation, but did
demonstrate difference starting at six hours post-operation. 10 In the study on
patients undergoing total hip replacement arthroplasty, no significant difference in
postoperative pain at emergence time or 30 minutes after surgery was displayed,
but differences did arise beginning at four hours post-operation. 13 This delayed
onset of magnesiums analgesic effects occurs because NMDA receptor antagonists
bind slowly to the receptor. According to Kim et al., magnesium will work faster and

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more effectively as an analgesic if it is given intrathecally or epidurally because this
makes it more available to the spinal cords NMDA receptors. 10

Risks of Hypermagnesemia:
During these studies, it was necessary for the researchers to monitor serum
magnesium levels as well as side effects that could possibly be as a result of
administration of a toxic amount of magnesium, called hypermagnesemia. None of
the studies previously mentioned demonstrated harmful side effects from the
amounts of magnesium the patients received. The Recommended Dietary Allowance
(RDA) for magnesium for a 19 to 30 year old male is 400 milligrams per day. The
RDA for a 19 to 30 year old female is 310 milligrams per day. The Tolerable Upper
Intake Level (UL) is 350 milligrams per day via supplementation only. The UL is the
amount of magnesium that can be safely consumed without adverse effects. No UL
has been set for magnesium consumed in natural form because no adverse effects
have been found. Exceeding the UL via supplementation may result in osmotic
diarrhea.14
Serum magnesium may be measured in millimoles (mmol) per liter. Normal
serum magnesium concentrations range between 0.75 and 0.95 mmol/L. 3 Minor
side effects like flushed skin, nausea, and headache may be present at serum
magnesium levels above 2 mmol per liter. Potentially life-threatening complications
(related to cardiovascular and neuromuscular systems) may arise at serum
magnesium concentrations above 5 mmol per liter. 13 The reports for two of the
aforementioned studies noted the serum magnesium levels of their patients. The
study on patients undergoing total hip replacement arthroplasty found that the
highest average serum magnesium concentration in patients during or after the

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operation was 1.31 mmol per liter and occurred immediately following the
procedure. The concentration decreased to 1.10 mmol per liter at one hour postoperation and normalized to .93 mmol per liter at 24 hours post-operation. While
these magnesium levels after the operation were higher than normal, they were not
near or above the 2 mmol per liter threshold where side effects may occur.
Therefore, the patients did not experience hypermagnesemia and its related signs
and symptoms.13 The study on women undergoing a Total Abdominal Hysterectomy
found the patients in the group given magnesium to have an average serum
magnesium level of 1.72 mmol per liter 10 minutes after magnesium administration
which is still below the level for hypermagnesia. 4

Conclusion:
As demonstrated by the aforementioned studies, magnesium is an important
bodily cation that functions as an effective postoperative analgesic. More studies
and research must be done to determine the exact mechanism by which
magnesium works to inhibit pain as well as the best dosage of magnesium to
administer. Successful studies on magnesium were able to reduce patient pain
which decreased intake of medicinal analgesics after the operation. The study of
methods to reduce pain-relieving drug intake following surgical procedures is
important to decrease side effects from, or addiction to, the drugs, as well as to
reduce the amount of money that must be spent to purchase the drugs. According
to the five aforementioned, successful studies, magnesium given in adequate
amounts, in addition to medicinal anesthesia, reduces pain without causing any of
its own side effects or putting patients at high risk for hypermagnesemia, as
compared to the control groups. Magnesiums analgesic effect and tendency to

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decrease patients needs for additional drugs to control pain postoperatively make it
a notable and worthwhile addition to operative routines.

Works Cited
1. Mukherjee, Kasturi, Anjan Das, Sandip Roy Basunia, Soumyadip Dutta, Parthajit
Mandal, and Anindya Mukherjee. "Evaluation of Magnesium as an Adjuvant in
Ropivacaine-induced Supraclavicular Brachial Plexus Block: A Prospective, Doubleblinded Randomized Controlled Study." Journal of Research in Pharmacy Practice 3.4
(2014): 123-29. Journal of Research in Pharmacy Practice. Medknow Publications,
Oct. 2014. Web. 12 Apr. 2015. This study focused on the effects of magnesium
sulfate in conjunction with a supraclavicular brachial plexus block. The study found
that magnesium sulfate prolongs the blockade of pain sensations and decreases the
use of analgesics postoperatively.

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2. Dietary Reference Intakes: For Calcium, Phosphorus, Magnesium, Vitamin D, and


Fluoride. Washington, D.C.: National Academy, 1997. Print. This is a book that has
been published online. It details the functions of magnesium in the body, its
bioavailability, and food sources.
3. "Magnesium." National Institutes of Health. N.p., 4 Nov. 2013. Web. 12 Apr. 2015. This
website provided basic information on magnesium. This information included
magnesium's function in the body, food sources, RDA, and UL.
4. Taheri, Arman, Katayoun Haryalchi, Mandana Mansour Ghanaie, and Neda Habibi
Arejan. "Effect of Low-Dose (Single-Dose) Magnesium Sulfate on Postoperative
Analgesia in Hysterectomy Patients Receiving Balanced General
Anesthesia." Anesthesiology Research and Practice (2015): n. pag. National
Institutes of Health. Web. 12 Apr. 2015. This study assessed the postoperative
analgesic effects of magnesium sulfate in women undergoing a total abdominal
hysterectomy. The study found that magnesium sulfate decreased both
postoperative pain and opioid consumption.
5. Jamero, Dana, Amne Borghol, Nina Vo, and Fadi Hawawini. "The Emerging Role of
NMDA Antagonists in Pain Management." Medscape. N.p., n.d. Web. 14 Apr.
2015. This source discussed how NMDA antagonists work. It discussed their method
of decreasing pain.
6. Bennett, GJ. "Update on the Neurophysiology of Pain Transmission and Modulation:
Focus on the NMDA-receptor." Opiods.com. MCP Hahnemann University, Jan. 2000.
Web. 14 Apr. 2015. This source detailed the mechanism of antagonism of NMDA
receptors. It discussed the relationship between NMDA activation and pain.
7. Wilder-Smith, C.H., R. Knpfli, and O.H.G. Wilder-Smith. "Perioperative Magnesium
Infusion and Postoperative Pain." Acta Anaesthesiologica Scandinavica 41.8 (1997):
1023-027. Wiley Online Library. Web. 8 May 2015. This 1996 study tested
magnesium's analgesic effects for patients undergoing a total abdominal

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hysterectomy (TAH). The study concluded that magnesium does not produce
analgesic effects for patients undergoing TAH, in conflict with the results of a 2014
study.
8. "Supraclavicular Brachial Plexus Block." New York School of Regional Anesthesia. N.p.,
20 Sept. 2013. Web. 14 Apr. 2015. This source detailed the steps of the
supraclavicular brachial plexus block. It discussed its primary use as a pain-blocker
for the upper extremities.
9. "Rescue Analgesic." Therapy of Pain. N.p., n.d. Web. 14 Apr. 2015. This website defined
rescue analgesic. It is defined as medication taken in addition to one's scheduled
pain medication regimen.
10. Kim, EM, MS Kim, SJ Han, BK Moon, EM Choi, EH Kim, and JR Lee. "Magnesium as an
Adjuvant for Caudal Analgesia in Children." Pediatric Anesthesia 24.12 (2014): 1231238. Wiley Online Library. Web. 12 Apr. 2015. This study assessed use of
magnesium as a postoperative analgesic in children undergoing inguinal
herniorrhaphy. The study found that magnesium paired with a local anesthetic
decreased pain as opposed to a local anesthetic alone.
11. Birbicer, H., N. Doruk, I. Cinel, S. Atici, D. Avlan, E. Bilgin, and U. Oral. "Could Adding
Magnesium as Adjuvant to Ropivacaine in Caudal Anaesthesia Improve
Postoperative Pain Control?" Pediatric Surgery International 23.2 (2007): 19598. Wiley Online Library. Web. 8 May 2015. This study tested magnesium's
analgesic effects in inguinal herniorrhaphy in children. The researchers concluded
that magnesium does not function as an analgesic in this type of operation. This
finding is in conflict with a more recent study.
12. Tamba, Bogdan I., Maria-Magdalena Leon, and Tudor Petreus. "Common Trace
Elements Alleviate Pain in an Experimental Mouse Model." Journal of Neuroscience
Research 91.4 (2013): 554-61. Wiley Online Library. Web. 12 Apr. 2015. This study
used a series of tests to evaluate the analgesic effects of magnesium21 chloride in

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mice. The study found that magnesium21 chloride decreases pain sensations in
mice.
13. Hwang, J.-Y., H.-S. Na, Y.-T. Jeon, Y.-J. Ro, C.-S. Kim, and S.-H. Do. "I.V. Infusion of
Magnesium Sulphate during Spinal Anaesthesia Improves Postoperative
Analgesia." British Journal of Anaesthesia104.1 (2009): 89-93. Oxford Journals. Web.
12 Apr. 2015. This study assessed the postoperative analgesic effects of magnesium
sulfate following total hip replacement arthroplasty. The study found magnesium to
decrease pain scores in patients without causing negative side effects.
14. "Dietary Reference Intakes: Elements." Institute of Medicine. The National Academies
Press, n.d. Web. 12 Apr. 2015. This was a chart published online listing the DRI and
UL for magnesium.

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