Smooth muscle spasm management

Introduction

Smooth muscle spasm, an involuntary contraction of a muscle, can occur in a variety of conditions, and each depends upon predisposing factors, the part involved, and the working environment of the body.¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012    When the hollow viscera are squeezed by the muscle spasm, significant pain can occur. For instance, smooth muscle in the intestinal wall can go into spasm, causing waves of pain called ‘colic’. Also, colicky pain which tends to be rhythmic may occur within the bile duct that empties the gallbladder and may develop after taking food.¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012  ^,2Muscle Spasms. Available at: http://www.medicinenet.com/muscle_spasms/article.htm. Accessed on 17-07-2012  

Similarly, muscles surrounding the esophagus can go into spasm when irritation occurs with reflux esophagitis or gastroesophageal reflux disease (GERD). Diarrhea can be associated with colicky pain, whereby the muscles within the colon wall undergo spasm just before a watery bowel movement.²  

Likewise, when kidney stones try to pass, the smooth muscles in the ureteral walls may undergo spasm and cause significant pain. Often the pain is associated with nausea and vomiting.²Muscle Spasms. Available at: http://www.medicinenet.com/muscle_spasms/article.htm. Accessed on 17-07-2012  

Signs and symptoms

Smooth muscle spasm will cause colicky pain that is usually rhythmic in nature. Nonetheless, the symptoms will largely depend upon the organ involved.²Muscle Spasms. Available at: http://www.medicinenet.com/muscle_spasms/article.htm. Accessed on 17-07-2012   In fact, considering gastrointestinal tract, intestinal motility disorders with abnormal intestinal contractions, such as spasms, describe a variety of disorders in which the gut has lost its ability to coordinate muscular activity because of endogenous or exogenous causes. Such disorders may be primary or secondary and may manifest in a variety of ways, with the following symptoms: abdominal distention, recurrent obstruction, severe abdominal colicky pain, severe constipation, intractable, recurrent vomiting.³Kuwajerwala NK. Intestinal Motility Disorders. Available at: http://emedicine.medscape.com/article/179937-overview. Accessed on 17-007-2012  

Indeed, spasm of the smooth muscle is a common pathogenetic mechanism in various colonic diseases, i.e. diverticular disease, irritable bowel syndrome, ulcerative colitis, non-occlusive ischemic colitis, and pseudomembranous colitis. The strength of the spasm producing increased pressure in the colonic lumen or wall and the length of time for which the colon has been affected are believed to determine the type of disease resulting.⁴Grimes DS. Refined carbohydrate, smooth-muscle spasm and disease of the colon. Lancet. 1976;1(7956):395-7.  

Diagnosis and investigations

Diagnostic evaluation of a patient with smooth muscle spasm usually begins with a history and physical examination. Also, it is helpful to know the circumstances surrounding the muscle spasm; for instance, the origin, duration and frequency, and if it is always the same muscle group of the body involved? In addition, information should be obtained concerning whether there have been any recent illnesses or whether any medications have been taken. Indeed, past medical history may give a clue for the reasons of muscle cramps.²Muscle Spasms. Available at: http://www.medicinenet.com/muscle_spasms/article.htm. Accessed on 17-07-2012  ⁵Wardhaugh A, Cosgroves M. The management of recurrent abdominal pain. Current Paediatrics 2001;11, 276-280.  ⁶Leung AKC. Acute abdominal pain in children. AAFP 2003;67:11.  

In general, physical examination may be useful in detecting underlying medical issues that may be helpful in making the diagnosis. For those having pain from smooth muscle spasm, the pain may be severe enough to present to an emergency department. Here, the history and physical examination will be directed to finding the source of the pain, while at the same time trying to control the symptoms promptly. Some patients with irritable bowel condition may also present with significant intestinal spasm.²Muscle Spasms. Available at: http://www.medicinenet.com/muscle_spasms/article.htm. Accessed on 17-07-2012  

Yet, for patients with recurrent spasm where the cause is not easily diagnosed by history and physical examination, testing may be needed to identify the potential causes. Largely, investigations depend on the source of pain, and the organ system involved. ²Muscle Spasms. Available at: http://www.medicinenet.com/muscle_spasms/article.htm. Accessed on 17-07-2012   Laboratory investigations should be tailored according to the patient’s signs, symptoms and clinical examination findings. Plain film abdominal radiographs are useful in cases of suspected intestinal obstruction or when perforation of a viscus in the abdomen is a concern.

Likewise, chest radiographs may help to rule out pneumonia. The choice of imaging study or an endoscopy as an initial test depends on clinical presentation.⁷Shashidhar H, Omar HA. Recurrent lower abdominal pain in older children and adolescents: Revised clinical approach. The Scientific World journal 2005;5:64-70.   Essentially, both clinical patterns of presentation and disease process as well as operational issues in emergency should govern the decision to use any particular investigation.

Treatment

Similar to the diagnosis, the treatment of smooth muscle spasm also depends upon the underlying cause.²Muscle Spasms. Available at: http://www.medicinenet.com/muscle_spasms/article.htm. Accessed on 17-07-2012    Often, pain control is initiated simultaneously with efforts to make the diagnosis; and the anti-spasmolytic treatment steps in at that time.

Role of an anti-spasmodic

Administration of an antispasmodic may have three different objectives:¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012  

• Symptomatic treatment of spasm due to a given syndrome, without being involved in its pathogenesis
• Spasmolytic drug may be a part of causal therapy if the spasm is the leading symptom or cause of the underlying disease
• Spasmolytics can be used for diagnostic purposes and for preoperative/postoperative medication (ureteral catheterization, X-Ray examination of gastrointestinal tract, gallbladder, kidney, etc.).

Anti-cholinergics as anti-spasmodics

Anti-cholinergic medications are thought to be helpful in spasmodic conditions through their effects on decreasing smooth muscle spasms in the gastrointestinal tract, which may produce symptoms such as pain. However, they are used more conservatively and their use is discouraged in patients with abdominal pain for fear of interfering with accurate evaluation and diagnosis; since they often mask the physical symptoms of “acute abdomen” making it difficult to achieve a rapid diagnosis and accurate management in emergency situations.

Moreover, the associated bothersome side-effects caused by anti-cholinergic agents, such as sedation, constipation, dryness of mouth, may interfere with diagnostic evaluation, and can be a hindrance for their long-term use. Their use is contraindicated in conditions like crohn’s disease and ulcerative colitis. Hence, need exists for a safe and effective agent that does not mask the symptoms of the underlying etiology, and does not interfere with the diagnosis.

Drotaverine – drug of choice for smooth muscle spasm management

Drotaverine may essentially be considered the drug of choice in the treatment of acute and chronic smooth muscle spasms and different pathological conditions accompanied by spastic pain, attributable to its characteristic properties (Box 1).¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012   The drug is well absorbed (90%) from all parts of the small intestine through linear absorption. Moreover, drotaverine and its metabolites can hardly penetrate the placental barrier.¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012  

After a single dose of 80mg the drug exhibited an absorption half life (t 1/2) of 12 minutes, and Cmax in plasma of the parent compound appeared 45 minutes after the administration showing its rapid absorption.⁸Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).   Also, 65% of the drug reaches unchanged in systemic circulation. In vitro, drotaverine is bound to human

plasma proteins. It is almost completely metabolized to O-demethyl and desethyl products, which are rapidly conjugated by glucoronic acid. Unchanged drotaverine can be detected in the bile only at extremely high doses.¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012  

The terminal elimination t1/2 of drotaverine is 16 hours after oral administration, while after intravenous (IV) administration the elimination t1/2 is about 2.4 hours.¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012  

Mechanism of action

Drotaverine has significant inhibitory effect on phosphodiesterase (PDE) enzyme. It inhibits PDE IV enzyme in vitro without inhibiting PDE III and PDE V. This is important since, functionally, PDE IV appears to be very important in reducing contractile activity of the smooth muscles, suggesting that selective PDE IV inhibitors might be useful in the treatment of hypermotility disorders and various diseases associated with spastic conditions of the gastrointestinal tract. Nonetheless, the PDE enzyme that hydrolyses cyclic AMP (cAMP) in myocardial and vascular smooth muscle cells is mainly PDE III isoenzyme, which explains why drotaverine is an effective spasmolytic agent without serious cardiovascular adverse effects.¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012  

The two metabolites of drotaverine in the bile (deoxy- and deoxy-desethyl metabolite) are 10-times more active in inhibiting PDE IV than drotaverine; perhaps being responsible for the excellent clinical efficacy of drotaverine in biliary spasm disorders.

Indications of drotaverine

The characteristic pharmacological profile makes drotaverine a potential spamolytic in a large number of indications with smooth muscle spasm (Table 1).¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012   Indeed, drotaverine has no serious adverse effects, and is well tolerated by all age groups.⁹Molnar DL. No-SPA-az-oxylogiai gyakarlatban (No-SPA in theoxyology practice) Budapest. SocioMed Kft. 1996; 1-27.  

Managing abdominal pain due to spasm

Being an isoquinoline derivative, drotaverine possess a powerful spasmolytic action on smooth muscle cells. In effect, the selective inhibitor of PDE IV has been found useful in spastic and motility disorders of the smooth muscle.10 In contrast to the general outlook that spasmolytics inhibit intestinal passage, preclinical evidence showed that at therapeutic concentrations drotaverine had no inhibitory effect on gastrointestinal motility. Moreover, it does not have any morphine or dextropropoxyphene like effect, and does not cause addiction.

Characteristically, the beneficial effect of oral drotaverine has been emphasized in therapy of spastic pain. Indeed, oral administration of drotaverine can help in prolonging pain-relief, and efficacy for the maintenance of spasmolysis.

Interestingly, in spastic pain due to duodenal and gastric ulcer, it has been observed that pain disappearance begins after 5-6 minutes in cases of spastic pain attributable to gastrointestinal ulcer; the effect completes within 12 minutes, giving complete relief to the patients. Furthermore, studies evaluating the prescription profile of drotaverine usage and its efficacy in different gastrointestinal indications give evidence of pain relief in 72% – 86% of patients.

A placebo-controlled trial with intramuscular (IM) administration showed successful disappearance of the acute pain in three main sub-clinical groups: biliary disorders; gastrointestinal diseases (ulcer, gastritis, etc); renal colic states. The results showed a 60% immediate pain relief with the active drug-group, whereas placebo was ineffective in 73% of the cases. It, therefore, clearly demonstrated that drotaverine is the first drug of choice in smooth muscle spasm of the biliary system, and should be supplemented with the appropriate antibiotic treatment and/or laparoscopic cholecystectomy.⁸Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).  

As an adjuvant treatment it can be used effectively and safely in gastric and duodenal ulcer, gastritis, enteritis, colitis, pyloric spasm, and irritable colon disease. An open label study with end points identified as the rate of patients that became symptom free (suffering gastric and duodenal ulcer, acute coli attack), efficacy rate was 78% and in 8 cases of peptic ulcer drotaverine was used orally as monotherapy: during the 5-20 days of treatment, every patient became complaint-free. Another eight cases of colitis and intestinal spasm were also treated with 80mg of drotaverine thrice daily and the treatment was successful.⁸Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).  

Urology

A very promising area of drotaverine administration is the calculous colics of the kidney and ureters. The presence of three different isoenzymes of PDE in human, of which the predominant was PDE IV, forms the basis of the usage of drotaverine in the spastic conditions of the ureter, i.e. ureterolithiasis, and to facilitate the passage of the small stones through the ureter. In nephrolithiasis, the initial IV therapy could be continued with oral administration for further prolongation of the effect.

An open-Iabelled study randomized the patients suffering from ureterolithiasis into two groups, drotaverine (n=71) and a conservative group (n=66) treated with rimazolium. When the stone was localized at the upper or central part of the ureter, no significant differences were found in spontaneous stone removal. Yet, the stones located in the lower part of the ureter could be removed significantly more successfully spontaneously with drotaverine treatment compared to the analgesic treated group. Also, it was shown that the size of the delivered calculi was significantly bigger in the drotaverine treated group, indicating that the effective spasmolysis makes possible the spontaneous removal of those stones. Together, it is important to note that other therapeutic modalities in the treatment of ureteral calculi should not be avoided like fluid intake, exercise and anti-biotic prophylaxis, etc.⁸Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).  

Emergency medicine

The anti-spasmodic and pain-killing effect of drotaverine does not mask the symptoms of “acute abdomen”; this may have relevant application in practice to achieve a rapid diagnosis. Additionally, it is free of the side-effects associated with anti-cholinergic anti-spasmodics such as dicyclomine etc. Thanks to its rapid absorption, onset of action, efficacy, wide therapeutic window, repetitiveness, possible co-administration with analgesics that possibly make it a favorite drug in emergency medicine. In practice, drotaverine could be given in cases without finalized diagnosis; pre-treatment in the emergency situation has been observed to result in decrease of pain and spasm, without interfering the association of correct diagnosis. Thus, this clearly shows that drotaverine is a highly potent and safe spasmolytic agent, suited for oral administration, and capable of relieving or preventing smooth muscle spasm of various organs.⁸Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).  

Gynecology and obstetrics

Drotaverine was found to be very effective in patients undergoing insertion of an intrauterine contraceptive device (IUCD). Moreover, in the pretreatment of hysterosalpingography, use of drotaverine results in radiological pictures having much better quality, avoiding the misleading interpretations because of transitory spasms in the uterine tube. Furthermore, the selective PDE IV inhibitor, drotaverine facilitates the dilatatory phase of uterine cervix.

The obstetrical significance of the administration of drotaverine is also very promising. The IV and/or IM administration of drotaverine in the terminal dilatatory phase of the uterine cervix resulted in a facilitated dilatation, shortening the time of cervical effacement in normal uncomplicated deliveries, and, finally, shortening the duration of labor. Also, it can be used in cases of epidural anesthesia, since it does not alter the activity of uterine contractions at the given dose.

Drotaverine is proposed to be used in active drug treatment strategy of management of the placental phase of the delivery in order to facilitate the procedure of placental delivery and to prevent the placental incarcerations.⁸Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).  

Pharmacoradiology

Anti-spasmodics are very useful in the differential diagnosis of some gastroenterological diseases in etiological imaging techniques. Drotaverine is frequently used in the premedication of esophagoscopy and gastroscopy and for the distension procedures of esophageal strictures.⁸Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).  

Co-administration with other drugs

Co-administration of analgesics is advantageous; the pain-killing effects are additive. The following analgesics were used successfully: metamizole, paracetamol, acetylsalicylic acid.¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012    However, cautious use is advocated when used with levodopa in parkinsonians, since the antiparkinson effect may be reduced while the tremor and rigidity may increase.¹No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012  ^,8Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).  

Conclusion

General practitioners when faced with any of the clinical manifestations of smooth muscle spasm have a very limited therapeutic inventory for spasm and pain relief. Anti-spasmodics are used in emergency and thereafter rapid diagnostic procedures results in deciding between conservative (drug) treatment and immediate surgical intervention.

Essentially, to have prompt diagnosis, it is important that the analgesic used does not mask the underlying pathology, a need well consistent with drotaverine application. The drug does not mask the symptoms of “acute abdomen”, and, thus, may be valuable both as initial drug used for pain-killing effect associated with spasmodic pain, and for maintenance of spasmolysis. It can be given effectively in cases without a final diagnosis to decrease pain and spasm, without interfering the association of correct diagnosis.

In conclusion, drotaverine is a highly potent and safe spasmolytic agent, capable of relieving or preventing smooth muscle spasm of various organs. It is free of the side-effects associated with the known anti-cholinergic anti-spasmodics like dicyclomine, and contributes very effectively, either alone or in combinations, in relieving painful spasms in a large variety of diseases of gastroenterological, urological, gynecological and obstetrical origin, and is the first drug of choice in the emergency medicine.

References

1. No-Spa (Drotaverine). Available at: http://www.tsconnect.info/index.php?option=com_content&view=article&id=4787:corp2001-215&catid=28&Itemid=492. Accessed on 17-07-2012
2. Muscle Spasms. Available at: http://www.medicinenet.com/muscle_spasms/article.htm. Accessed on 17-07-2012
3. Kuwajerwala NK. Intestinal Motility Disorders. Available at: http://emedicine.medscape.com/article/179937-overview. Accessed on 17-007-2012
4. Grimes DS. Refined carbohydrate, smooth-muscle spasm and disease of the colon. Lancet. 1976;1(7956):395-7.
5. Wardhaugh A, Cosgroves M. The management of recurrent abdominal pain. Current Paediatrics 2001;11, 276-280.
6. Leung AKC. Acute abdominal pain in children. AAFP 2003;67:11.
7. Shashidhar H, Omar HA. Recurrent lower abdominal pain in older children and adolescents: Revised clinical approach. The Scientific World journal 2005;5:64-70.
8. Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).
9. Molnar DL. No-SPA-az-oxylogiai gyakarlatban (No-SPA in theoxyology practice) Budapest. SocioMed Kft. 1996; 1-27.
10. Misra SC, Pandey RM. Efficacy of drotaverine in irritable bowel syndrome: a double blind, randomized, placebo-controlled clinical trial. The American Journal of Gastroenterology 2000;95:2544.