Microstructural Changes after Intramuscular Injection of Lidocaine and Dexamethasone
Seong-Min Jang, D.D.S., Kyong-Eun Lee, D.D.S.,M.S.D.
Department of Oral Medicine, Institution of Oral Bioscience, College of Dentistry, Chonbuk National University
A trigger point injection (TPI) has been reported to have an immediate analgesic effect, and to be one of the most widely employed treatment methods of myofascial pain. There are normal saline, local anesthetics, and steroids as the solutions frequently used in TPI. They can be used separately or in combination. Local anaesthetics have myotoxicity in proportion to its concentration.
The purpose of this study was to evaluate microstructural changes in point of the myotoxic effects of the combined solution of lidocaine and dexamethasone (a local anesthetic and a steroid) after being injected into the muscle of BALB/c mice. And this study tested solutions with various concentration separately and in combination, to find out proper concentration of solution without muscular tissue damage.
This study shows that lidocaine and dexamethasone combination is not histologically myotoxic in case of the concentration of lidocaine less than 1.5%. Also it is suggested from this study that this combined solution will have an analgesic and anti-inflammatory effect. Hereafter continuous study should be performed to reveal that these results can be applied to human when lidocaine and dexamethasone combination is used as an injection modality of TrP treatment.
Key words : myofascial pain, trigger point injection, dexamethasone, lidocaine
1)
Ⅰ. INTRODUCTION
There are many patients who complain of functional limit and discomfort due to myofascial pain among patients with orofacial pain and temporomandibular disorders. Myofascial pain is a regional myogenous pain condition characterized by trigger point (TrP) which is exquisitely tender point in a taut band of muscle
1). Various kinds of physical
Corresponding Author: Kyong-Eun Lee Department of Oral Medicine
School of Dentistry, Chonbuk National University 664-14 Dok Jin-Dong, Dok Jin-Gu, Chonju 561-756, Korea
E-mail: [email protected] received: 2004-11-20
treatment modalities are useful in these symptoms
2,3), but most of them need time to take effect. On the other hand, a trigger point injection (TPI) has been reported to have an immediate analgesic effect
4-6), and to be one of the most widely employed treatment methods of myofascial pain syndrome
7,8).
The mechanism of TPI is not clarified yet, but there are several hypotheses. Not only direct destruction of TrP from dry needling, but also chemical pain control and anti-nociceptive system through descending inhibitory pathway were suggested
9). There are normal saline, local anesthetics, and steroids as the solutions frequently used in TPI
10). They can be used separately or in combination
11-13).
Occasionally, these solutions may cause toxicity.
Local anaesthetics have systemic toxicity, so there is a maximum dose
14). They can increase myotoxicity in proportion to its concentration.
Procaine, tetracaine, lidocaine, bupivacaine, etidocaine, chloroprocaine, dibucaine, and piperocaine as local anaesthetics were experimented about myotoxicity
15,16). When the mixture of bupivacaine and triamcinolone was injected, it delayed healing of muscle
17).
This study was focused on microscopic changes after an intramuscular injection of a combination of local anesthetic and steroid applied to TPI. And so lidocaine and dexamethasone were selected in this experiment. Lidocaine is frequently used in dental clinics, so it can be obtained easily. Dexamethasone, one of the most potent anti-inflammatory agent, can be mixed easily with dental lidocaine. It is necessary to find out the proper concentration of solutions which minimizes myotoxicity before being used in TPI.
In order to evaluate a microstructural changes in point of the myotoxic effects of a combination of lidocaine and dexamethasone, a microscopic survey after being injected intramuscularly into BALB/c mice was performed in this study. And this study tested solutions with various concentration separately and in combination, to find out proper concentration of solution without muscular tissue damage.
Ⅱ. MATERIALS AND METHODS
This study was conducted on sixty three BALB/c mice of eight-week-old females which were obtained from Da-mul science (Dae-geon, Korea) and the mice were kept caged for one week before the experiment. Experimental animals were largely divided into two groups of single solution injection group and combined solution injection group. The former was subdivided into three groups, and the latter was into four groups as follows, and each group was consisted of nine animals:
1. Single solution injection group
⑴ Normal Saline (NS) group ⑵ Dexamethasone (DM) group
- Dexamethasone disodium phosphate 5 mg/mL
(Choongwae Injection 1 mL, Korea) ⑶ 2.0% Lidocaine (2.0% Li) group - Lidocaine Hydrochloride 20 mg/mL (Huons Injection 1.8 mL, Korea) 2. Combined solution injection group
⑴ 1.0% Lidocaine/Normal Saline (1.0% LiNS) group
- Mixed 0.2 mL 2.0% Lidocaine and 0.2 mL Normal Saline
⑵ 1.5% Lidocaine/Normal Saline (1.5% LiNS) group
- Mixed 0.3 mL 2.0% Lidocaine and 0.1 mL Normal Saline
⑶ 1.0% Lidocaine/Dexamethasone (1.0% LiDM) group
- Mixed 0.2 mL 2.0% Lidocaine and 0.2 mL Dexamethasone
⑷ 1.5% Lidocaine/Dexamethasone (1.5% LiDM) group
- Mixed 0.3 mL 2.0% Lidocaine and 0.1 mL Dexamethasone
0.1 mL solution was injected into the right tibialis anterialis of each animal with a 30-gauge needle.
The animal was held firmly by one man and
injected by the other man. Three animals were
sacrificed at 1, 7, and 14 days after injection in each
group. The tibialis cranialis was removed from the
animals, fixed in 10% formalin solution, embedded
in paraffin, serially sectioned with three ㎛ thick,
and stained with hematoxylin-eosin and Van-
Gieson. The specimen slides were examined under
light microscope (Axiovert 25, Carl Zeiss, Germany)
on field of 25 and 100 magnification.
Ⅲ. RESULTS 1. Single solution injection group
There were low lymphocytic infiltrations and transient focal muscle fiber lysis in NS group after 1 day. Muscle fibers recovered from lysis and lymphocytic infiltrations returned to normal state after 7 days (Fig. 1～4).
There was more lysis of muscle fibers in DM group than in the other groups, but lymphocytic infiltrations did not increase after 1 day. Muscle fibers regenerated from lysis after 7 days(Fig. 5～8).
There were high lymphocytic infiltrations into the lysed muscle fibers in 2.0% Li group after 1 day. The lysed muscle fibers were on recovering state after 7 days: stained with hematoxylin intensively, incomplete muscle fiber structure, and fibrous change (pink colored in Van-Gieson stain).
Lymphocytic infiltrations after 7 days were same as that after 1 day (Fig. 9～12).
It was found that muscle fiber lysis occurred in all groups after 1 day, but NS group and DM group regenerated after 7 days except 2.0% Li group.
2.0% Li group after 7 days was stained intensively by hematoxylin in the lysed muscle fibers, and had fibrous remnants besides incompletely recovered fibers (Fig. 11, 12). After 14 days, all groups reco- vered to normal state (Fig. 25～27).
2. Combined solution injection group
Lymphocytic infiltrations into the lysed muscle fibers of 1.0% LiDM and 1.5% LiDM groups were less than 1.0% LiNS and 1.5% LiNS groups after 1 day. After 7 days, the former were less than the latter in lymphocytic infiltration and fibrous change
(Fig. 13～24).
There were more lymphocytic infiltrations into the lysed muscle fibers in 1.5% LiNS group than in 1.0% LiNS, 1.0% LiDM and 1.5% LiDM group after 1 day. After 7 days, the muscle fibers of 1.5% LiNS group were on recovering state with more lympho- cytic infiltrations and fibrous changes than other
groups (Fig. 13～24).
It was found that muscle fiber lysis occurred in all groups after 1 day, but 1.0% LiNS group, 1.0%
and 1.5% LiDM group regenerated after 7 days except 1.5% LiNS group. 1.5% LiNS group after 7 days was stained intensively by hematoxylin in the lysed muscle fibers, and had fibrous remnants besides incompletely recovered fibers (Fig. 17, 18).
After 14 days, all groups recovered to normal state (Fig. 28～31).
Ⅳ. DISCUSSION
Several hypotheses were proposed to explain TrP mechanism: energy crisis hypothesis, pain- spasm- pain cycle hypothesis, muscle spindle hypothesis, neuropathic hypothesis, and fibrotic scar tissue hypothesis
18). Among them, the energy crisis hypothesis has been the most accepted until now.
The basic concept of the energy crisis hypothesis is explained as follows. An increase in the calcium concentration outside the sarcoplasmic reticulum is possibly due to the mechanical rupture of either the sarcoplasmic reticulum or of the muscle cell membrane (sarcolemma). A sufficient increase in calcium would maximally activate contraction between actin and myosin. The sustained contractile activity of the sarcomeres would markedly increase metabolic demands and squeeze the rich network of capillaries that supply the nutrition and oxygen needs of that region. Circulation in a muscle fails during a sustained contraction that is more than 30% to 50% of maximum effort. This combination of increased metabolic demand and impaired metabolic supply could produce a severe but local energy crisis
18).
In addition, severe local hypoxia and a tissue energy crisis would be expected to stimulate the production of vasoreactive substances, which could sensitize local nociceptors. Thus, this could make central sensitization
9).
This hypothesis accounts for the effectiveness of
essentially any technique that elongates the TrP
portion of the muscle to its full stretch length-even
briefly, which could break the cycle that includes energy-consuming contractile activity
19). Continued activity of the actin-myosin interaction depends on physical contact between the actin and myosin molecules, which occurs fully when the sarcomere is approximately midlength or less. The molecules lose overlap contact at full length. With the cessation of contractile activity because of actin- myosin separation, both energy consumption and compression of capillaries would be relieved. This opportunity to restore energy reserves could help to block critical steps in the energy-crisis cycle.
Sometimes, this simple stretching therapy (mouth-opening exercise) is restricted because of strong contractile force induced by stretching pain.
At that time, TPI has immediate analgesic characteristics
4), then stretching is capable. There are several solutions frequently used in TPI: normal saline, local anaesthetics, steroids
10). The chief concern in this study was the combined solution of lidocaine and dexamethasone among these solutions.
Lidocaine is frequently applied in dental clinics, and it can be obtained easily. Dexamethasone is one of the most potent anti-inflammatory agents, and can be mixed easily with dental lidocaine.
These solutions can cause toxic effects to muscles
14,20). And so this study brought focus into lidocaine and dexamethasone. It has been reported that lidocaine has myotoxicity if its concentration exceeds one percent
21-23)and dexamethasone has an anti-inflammatory effect
24). Therefore this study was interested in toxicity levels and microstructural changes after an intramuscular injection of these solutions. 1.0% and 1.5% lidocaine mixed with dexamethasone or normal saline, 2.0% lidocaine, dexamethasone, and normal saline were tested on animal muscles.
It was observed in this experiment that there were less lymphocytic infiltrations in the 1.0%
LiDM and 1.5% LiDM groups than in the 1.0%
LiNS and 1.5% LiNS groups after 1 day. After 7 days, the muscle fibers of the 1.5% LiNS group had incomplete muscle fiber structure and focal fibrous changes with lymphocytic infiltrations, but the 1.5%
LiDM group did not.
These results shows that lidocaine above 1.5 % has the myotoxicity. In the lidocaine plus dexame- thasone, dexamethasone had an anti-inflammatory effect without additional myotoxicity if the concentration of lidocaine was less than 1.5%.
If TPI has an immediate analgesic effect, stretching pain can be avoided and the contracted knot of muscle can be fully stretchable. Then, maximum mouth opening can be obtained, and this stretching can remove TrP.
In addition, these solutions could lyse the muscle fibers of contracted knot for a while, and the lysed muscle fibers were reconstructed afterward. It is supposed that the contracted muscle fibers will be repaired into the normal state. This should be further evaluated by an electromicroscopic study of TrP lysis
If dexamethasone is mixed with lidocaine less than 1.5%, this mixed solution will not be histologically myotoxic and have an anti- inflammatory effect besides an analgesic effect. It was concluded that this mixed solution has additional benefits than an individual solution.
This study was not conducted on human model.
So it was suggested that further study on the effect of mixed solution of lidocaine and dexamethasone in human model should be performed because the myotoxicity is different by species and muscle types. It will be necessary to find out whether the effect of muscle fiber lysis can repair the contracted knot (TrP) or not.
V. CONCLUSIONS
The purpose of this study was to evaluate
microstructural changes in point of the myotoxic
effects of the combined solution of lidocaine and
dexamethasone (a local anesthetic and a steroid)
after being injected into the muscle of BALB/c
mice. And this study tested solutions with various
concentration separately and in combination, to find
out proper concentration of solution without
muscular tissue damage.
The myotoxicity was weak and transient in lidocaine/dexamethasone group when lidocaine concentration was under 1.5%. The transient muscle fiber lysis was same as that of normal saline group. The lysed fibers recovered to normal structure after 7 days.
The fibrous changes of the muscle fibers and the lymphocytic infiltrations in the lysed muscle fibers were less significant in lidocaine/dexamethasone group than lidocaine/normal saline group when lidocaine was the same concentration. So it could be found that lidocaine and dexamethasone combination has an anti-inflammatory effect, as it was compared to lidocaine and normal saline combination.
This study shows that lidocaine and dexame- thasone combination is not histologically myotoxic in case of the concentration of lidocaine less than 1.5%. Also it is suggested from this study that this combined solution will have an analgesic and anti- inflammatory effect. Hereafter continuous study should be performed to reveal that these results can be applied to human when lidocaine and dexamethasone combination is used as an injection modality of TrP treatment.
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국문요약
Lidocaine과 dexamethasone 혼합용액의 근육내 주사 후 조직학적 변화
전북대학교 치과대학 구강내과학교실 및 구강생체과학연구소
장성민․이경은
측두하악장애 및 구강안면통증 환자들 중 근막통증에 의한 기능제한이나 통증을 호소하는 경우를 흔히 볼 수 있다. 근막통 증환자를 치료할 때 여러 가지 물리치료가 유용하지만, 즉각적인 통증완화효과를 나타내는 발통점주사요법이 근막통증의 치 료로서 널리 적용되고 있다. 발통점주사요법에 흔히 사용하는 화학약제로 생리식염수, 국소마취제, 스테로이드 등이 있으며, 국소마취제는 근육에 대한 부작용이 보고되어 있어 사용상 주의가 필요하다. 이 연구는 상품화된 lidocaine과, dexamethasone 주사제의 혼합용액을 근육내 주사한 후 조직학적 변화를 관찰함으로써 근육에 대한 위해성 여부를 평가하고 자 하였다. 또한 용액의 농도에 따라 각각 조직학적 변화를 관찰함으로써 위해성이 없는 적정한 농도를 제시하고자 하였다.
이 연구에서는 생후 9주된 BALB/c 생쥐 (자성) 63마리를 7군으로 분류하여, 앞정강근 (전경골근, tibialis cranialis) 에 각각 생리식염수, dexamethasone, 2.0% lidocaine, 생리식염수와 혼합한 1.0% lidocaine, 생리식염수와 혼합한 1.5% lidocaine, dexamethasone과 혼합한 1.0% lidocaine, dexamethasone과 혼합한 1.5% lidocaine을 주사하였다. 그 후 1일, 7일, 14일째에 희생시켜 실험부위를 절취한 후 조직절편을 만들어 HE염색과 Van-Gieson염색을 거쳐 광학현미경으로 관찰하여 다음의 결 론을 얻었다.
Lidocaine과 dexamethasone의 혼합용액을 근육내 주사하였을 때, lidocaine의 농도가 1.5% 이하인 경우 조직학적으로 유해 하지 않았으며, 통증완화효과와 항염증작용을 동시에 기대할 수 있을 것으로 생각된다. 향후 상기 혼합용액을 발통점주사요 법의 약제로 사용할 경우, 인체에서도 동일한 결과가 나올 것인가에 대해서는 추가적인 연구가 필요하다.
주제어 : 근막통증, 발통점주사요법, dexamethasone, lidocaine
23. Burke GW, Fedison JR, Jones CR. Muscle degeneration produced by local anesthetics. Va Dent J 1972;49:33-37.
24. Simons DG, Travell JG, Simons LS. Apropos of all muscles. In Eric P. Johnson(Ed). Travell & Simons' Myofascial Pain and Dysfunction : The Trigger Point Manual. Vol. 1. Baltimore, 1999, Williams & Wilkins, pp. 94-177.
EXPLANATION OF FIGURES
Fig. 1. NS group, 1 day after injection, H&E stain, ×25 Fig. 2. NS group, 1 day after injection, H&E stain, ×100 Fig. 3. NS group, 7 days after injection, H&E stain, ×25 Fig. 4. NS group, 7 days after injection, H&E stain, ×100 Fig. 5. DM group, 1 day after injection, H&E stain, ×25 Fig. 6. DM group, 1 day after injection, H&E stain, ×100 Fig. 7. DM group, 7 days after injection, H&E stain, ×25 Fig. 8. DM group, 7 days after injection, H&E stain, ×100 Fig. 9. 2.0% Li group, 1 day after injection, H&E stain, ×25 Fig. 10. 2.0% Li group, 1 day after injection, H&E stain, ×100 Fig. 11. 2.0% Li group, 7 days after injection, H&E stain, ×100 Fig. 12. 2.0% Li group, 7 days after injection, Van-Gieson stain, ×100 Fig. 13. 1.0% LiNS group, 1 day after injection, H&E stain, ×100 Fig. 14. 1.0% LiNS group, 7 days after injection, H&E stain, ×100 Fig. 15. 1.0% LiNS group, 7 days after injection, Van-Gieson stain, ×100 Fig. 16. 1.5% LiNS group, 1 day after injection, H&E stain, ×100 Fig. 17. 1.5% LiNS group, 7 days after injection, H&E stain, ×100 Fig. 18. 1.5% LiNS group, 7 days after injection, Van-Gieson stain, ×100 Fig. 19. 1.0% LiDM group, 1 day after injection, H&E stain, ×100 Fig. 20. 1.0% LiDM group, 7 days after injection, H&E stain, ×100 Fig. 21. 1.0% LiDM group, 7 days after injection, Van-Gieson stain, ×100 Fig. 22. 1.5% LiDM group, 1 day after injection, H&E stain, ×100 Fig. 23. 1.5% LiDM group, 7 days after injection, H&E stain, ×100 Fig. 24. 1.5% LiDM group, 7 days after injection, Van-Gieson stain, ×100 Fig. 25. NS group, 14 days after injection, H&E stain, ×100
Fig. 26. DM group, 14 days after injection, H&E stain, ×100 Fig. 27. 2.0% Li group, 14 days after injection, H&E stain, ×100 Fig. 28. 1.0% LiNS group, 14 days after injection, H&E stain, ×100 Fig. 29. 1.5% LiNS group, 14 days after injection, H&E stain, ×100 Fig. 30. 1.0% LiDM group, 14 days after injection, H&E stain, ×100 Fig. 31. 1.5% LiDM group, 14 days after injection, H&E stain, ×100 Fig. 32. Not injected, H&E stain, ×100
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