Regulations Amending the Narcotic Control Regulations (Tramadol): SOR/2021-43

Canada Gazette, Part II, Volume 155, Number 7

Registration

SOR/2021-43 March 18, 2021

CONTROLLED DRUGS AND SUBSTANCES ACT

P.C. 2021-156 March 17, 2021

His Excellency the Administrator of the Government of Canada in Council, on the recommendation of the Minister of Health, pursuant to subsection 55(1) footnote a of the Controlled Drugs and Substances Act footnote b, makes the annexed Regulations Amending the Narcotic Control Regulations (Tramadol).

Regulations Amending the Narcotic Control Regulations (Tramadol)

Amendment

1 The schedule to the Narcotic Control Regulations footnote 1 is amended by adding the following after item 18.1:

19 Tramadol (2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol), its salts, isomers and salts of isomers and the following derivatives of tramadol and the salts, isomers and salts of isomers of those derivatives:

Coming into Force

2 These Regulations come into force on the first anniversary of the day on which they are published in the Canada Gazette, Part II.

REGULATORY IMPACT ANALYSIS STATEMENT

(This statement is not part of the Regulations or the Order.)

Issues

Tramadol is a synthetic opioid analgesic that has been marketed in Canada since 2005. It has been regulated under the Food and Drugs Act (FDA), and is available by prescription only. Like other opioid analgesics, while tramadol can provide effective pain relief for some patients, it has potential for problematic use, footnote 2 and chronic use of tramadol can lead to tolerance and dependence. Tramadol can also cause harmful adverse effects that pose risks to human health, which can be fatal in some cases. Tramadol is suspected to have contributed to 27 reported deaths in Canada between 2006 and March 2020.

The crisis of overdoses and deaths caused by opioids is of national concern in Canada. Canada is the world's second-largest consumer of prescription opioids per capita, and there have been increasing concerns related to prescription opioids due to their potential for diversion and problematic use, both within Canada and globally. While problematic use of tramadol has not contributed significantly to the opioid crisis in Canada, it is a significant and growing public health concern in other countries, and is a potential threat to the health and safety of Canadians.

Unlike most opioid analgesics, tramadol was not controlled under the Controlled Drugs and Substances Act (CDSA) or regulated under the Narcotic Control Regulations (NCR). Controlling tramadol will strengthen Health Canada's (HC or the Department) oversight of legitimate activities with tramadol, and facilitate detection and prevention of diversion. It will also enable Canadian law enforcement agencies to take enforcement action against a broader range of unauthorized activities with tramadol, such as the seizure of unauthorized shipments of tramadol. This will help to mitigate the risk of problematic tramadol use emerging as a significant threat to the health and safety of Canadians.

Background

Pharmacology

Opioids are a class of drugs that have analgesic properties, and the proper use of prescription opioids can be helpful for managing pain for some patients. However, opioids can also produce effects, such as euphoria, that create the potential for problematic use. Opioids can also cause harmful adverse effects, including potentially fatal respiratory depression, and can produce tolerance and dependence with chronic use.

By itself, tramadol is a weak opioid. When ingested, tramadol is partly broken down into the more potent opioids, O-desmethyltramadol (M1) and N,O-didesmethyltramadol (M5). Most of tramadol's opioid-related effects are attributable to M1, with tramadol itself contributing to some extent. M5 is not produced in sufficient quantity to contribute significantly to the aforementioned effects; however, if it is produced outside the body in sufficient quantities, it can be converted to M1 through a simple chemical process.

Unlike most opioids, tramadol also has properties as a serotonin and norepinephrine reuptake inhibitor (SNRI). These properties contribute to tramadol's analgesic effect, but can also cause additional harmful adverse events such as seizures and serotonin syndrome, footnote 3 which can be fatal in some cases. The likelihood of these events increases with dosage, or if tramadol is taken in combination with other drugs that affect serotonin.

The potency of tramadol's SNRI and opioid-related effects also depends on how much of the drug is converted to M1 before it reaches the brain. This can vary significantly due to genetic factors, and some individuals will experience much more potent (or much weaker) opioid effects from the same dose of tramadol compared to the average patient. It is not feasible to identify those individuals prior to initiating treatment, which can have implications for patient safety.

Medical use

Tramadol is used primarily as an analgesic and is considered to be a weak opioid. It can be administered in dosages that provide pain relief comparable to low therapeutic doses of more potent opioid analgesics, but cannot be safely taken in higher doses due to the risk of SNRI-related adverse effects.

Tramadol is available in Canada by prescription only, and is authorized for human and veterinary use. It is indicated for the treatment of moderate to moderately severe pain, but is also known to be prescribed “off-label” as a treatment for other conditions, most commonly for ejaculation dysfunction. Taking into account average prescription sizes, footnote 4 tramadol has been the fifth most prescribed opioid and one of six opioids that accounted for 98% of opioid prescriptions in Canada between 2015 and March 2020 (inclusive). While the prescription of opioid analgesics (e.g. codeine, oxycodone, hydromorphone) has declined between 2015 and 2019, tramadol prescriptions increased until 2017 and have remained steady since.

Regulatory framework

The CDSA is the means by which Canada fulfills its obligations under the United Nations Single Convention on Narcotic Drugs, 1961, the United Nations Convention on Psychotropic Substances, 1971, and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988. These conventions form the basis for the current global drug control system. The CDSA provides for the control of substances that can alter mental processes, and that may produce harm to health and to society when diverted or misused, and chemical precursors that can be used to synthesize these substances.

The CDSA prohibits certain activities with the substances listed in its schedules, unless they are authorized by the CDSA regulations, or through an exemption pursuant to subsection 56(1) of the Act. The CDSA also specifies the range of penalties associated with the conduct of illegal activities with controlled substances and chemical precursors.

The CDSA regulations define the conditions for conducting authorized activities with the controlled substances listed in their schedules. Opioid analgesics are generally scheduled under the NCR and are subject to the corresponding requirements. For example, dealers licensed to produce, distribute, import and export substances scheduled under the NCR must comply with requirements for secure handling and storage, record keeping, and reporting of loss and theft of those substances. Further requirements for secure storage of controlled substances at licensed dealer sites are outlined in HC's Directive on Physical Security Requirements for Controlled Substances and Drugs Containing Cannabis (Security Directive). Non-compliance with these requirements may result in the suspension or revocation of a licence or permit, or a referral for criminal prosecution.

This framework protects public health and maintains public safety by balancing the need for access to these substances for legitimate medical, scientific, and industrial purposes, and the need to minimize the risk of diversion to illegal markets and uses.

Scheduling history

In 2007, HC published a Notice of Intent in the Canada Gazette, Part I, indicating the Department's intent to add tramadol to Schedule I to the CDSA and to the schedule to the NCR.

While health professional associations and provincial and territorial licensing bodies were generally supportive of the proposed amendments, most of the feedback provided by other stakeholders raised concerns that scheduling was not warranted.

HC subsequently commissioned external reviews of tramadol's chemistry and pharmacology, which were completed in 2008. After considering the reviews' findings and the data available at the time, the Department did not proceed to control tramadol.

Current status

There is now more evidence indicating that high doses of tramadol could have potential for problematic use comparable to some opioids controlled under Schedule I to the CDSA, such as meperidine (marketed as Demerol®). Since 2006, tramadol is suspected to have contributed to 94 adverse events related to problematic use, footnote 5 dependence or withdrawal reported in Canada (as of March 2020), and to over 9 829 reported internationally (as of August 2020). Problematic tramadol use is also reported to be a serious and growing public health concern for many countries, particularly in Africa and Western Asia.

There have also been nine reported deaths in Sweden linked to the use of “herbal krypton,” a preparation that included M1. These reports found no evidence for the presence of tramadol, which implies that M1 may have been produced for direct consumption.

Although the available evidence does not suggest that M5 has significant potential for problematic use, it does present a risk due to the fact that it can be easily converted into M1.

Objective

By placing legislative controls on tramadol, M1 and M5, the amendments will serve to help mitigate the health and safety risks of problematic use of these substances. The amendments provide law enforcement officers with the power to take action against any unauthorized activities with these substances and strengthen the monitoring of authorized activities, including their use for medical and other legitimate purposes. Additionally, the amendments complement existing initiatives implemented under the Canadian drugs and substances strategy (CDSS), which aims to balance public health and public safety objectives through the four pillars of prevention, treatment, harm reduction, and enforcement.

Description

Order amending Schedule I to the CDSA

This Order amends Schedule I to the CDSA by adding tramadol, M1 and M5, and the salts, isomers, and salts of isomers of tramadol, M1 and M5 to the list of substances.

Regulations amending the schedule to the NCR

The Regulations amend the schedule to the NCR to add tramadol, M1 and M5, and the salts, isomers, and salts of isomers of tramadol, M1 and M5 to the list of substances.

Regulatory development

Consultations prior to prepublication of the proposed amendments in the Canada Gazette, Part I

On June 16, 2018, HC published a notice to interested parties (NTIP) in the Canada Gazette, Part I, indicating the Department's intent to add tramadol to Schedule I to the CDSA and to the Schedule to the NCR. The Department received feedback from 20 respondents, most of whom expressed support for the proposed amendments.

Health care professionals, organizations, and regulatory bodies

Feedback from health care professionals and related organizations was generally supportive. Many of these stakeholders stated that tramadol can produce euphoria and dependence similar to other opioids, and that it should be regulated in the same way as those substances.

Some stakeholders also suggested that controlling tramadol could help dispel misperceptions about its safety for medical use compared to other prescription opioids. Some also noted that tramadol could pose additional risks for some populations because of its variable potency.

Industry

Stakeholders from industry commented that scheduling tramadol would create regulatory burdens for firms that supply tramadol products, such as additional import time required to obtain import permits. They also noted that some firms would need to make changes to their infrastructure to store inventories of tramadol in compliance with the physical security requirements for substances regulated under the NCR.

While none of these stakeholders objected to controlling tramadol under the CDSA, some noted that companies that did not work with substances regulated under the NCR might choose to discontinue their activities with tramadol rather than comply with the new requirements. One also suggested that the physical security measures required for products regulated under the NCR were not necessary to prevent diversion of tramadol, while others emphasized the importance of allowing companies sufficient time to implement the required changes to avoid disruptions in supply.

Based on the input received and further discussions with industry, these amendments will take effect 365 days after their publication in the Canada Gazette, Part II.

Wildlife rehabilitation

One organization involved in wildlife rehabilitation indicated that they use tramadol to provide analgesia for sick and injured animals. Most wildlife rehabilitators are not licensed veterinarians, and they rely on veterinarians to provide them with prescription drugs to administer to the animals in their care following protocols established by the veterinarian. The organization believes that, if tramadol was controlled, their veterinarian would no longer be able to prescribe tramadol to have on hand in case of an emergency (e.g. to treat an injured animal hit by a car). The organization expressed concern that some wildlife rehabilitators would not be able to provide adequate analgesia to the animals in their care if they did not have access to an easy to administer, non-controlled opioid analgesic such as tramadol.

Veterinarians prescribe drugs to individual animal patients in a similar manner that doctors do for their human patients. However, when there are large numbers of animal patients (e.g. a herd of cattle that may require treatment), veterinarians may also prescribe for the entire herd. This is how drugs are often prescribed to wildlife rehabilitators to treat the animals in their care. Non-controlled alternatives to tramadol available to wildlife rehabilitators include analgesics such as non-steroidal anti-inflammatory drugs (e.g. meloxicam, carprofen); alpha-2 adrenergic receptor agonists (e.g. medetomidine); local anesthetics (e.g. lidocaine). These alternative drugs may have additional safety concerns and often require additional skills to administer safely in comparison to tramadol.

Veterinary use of controlled pharmaceutical drugs is regulated at the federal, provincial and territorial levels. In 2018, HC consulted provincial and territorial veterinary licensing authorities to determine if any existing regulations or practice guidelines could prevent veterinarians from providing wildlife rehabilitators with controlled substances. Five provincial licensing bodies responded, but only one identified a potential barrier to this practice in their jurisdiction. The potential barrier stems from a professional practice regulation that prohibits veterinarians from dispensing controlled substances and narcotics to treat free-ranging wildlife. The animal must be under the direct care of the veterinarian to be treated with controlled substances. The provincial veterinary licensing authority indicated that it was working with veterinarians to determine an acceptable path forward, should tramadol become controlled under the CDSA. The veterinary licensing authorities that responded to the consultation request indicated support for the scheduling of tramadol.

Patients

Some respondents raised concerns that controlling tramadol could create barriers to access for patients. One respondent that supported controlling tramadol also stressed the importance of hearing patient concerns, and of ensuring that access to appropriate pain management is not compromised. Some respondents that did not support the proposal provided anecdotes about tramadol's therapeutic value, or questioned the evidence of tramadol's actual or potential for problematic use.

HC has reviewed the evidence of tramadol's potential for problematic use, and has found that it may be comparable to some controlled opioids, which is supported by reports of problematic use from other jurisdictions (e.g. Africa, Asia).

Tramadol is already identified as a prescription drug on HC's Prescription Drug List (PDL). Once the amendments are in force, patients will continue to obtain tramadol from a practitioner or by written prescription, but verbal prescriptions and refills will no longer be permitted. This is not expected to have a significant impact on patient access.

HC has consulted with clinicians and researchers involved in the treatment of chronic pain and pain management, as well as patients living with chronic pain. The Department recognizes that some patients who suffer from chronic pain have experienced increased stigma as a result of the attitudes and beliefs around opioid use in the context of the current opioid crisis. The Department has also heard from patients living with chronic pain who have encountered inconsistencies in treatment services. HC is committed to working with Canadians living with pain, clinicians and researchers to increase knowledge and implementation of best practices in pain management and to improve the health of Canadians experiencing pain.

Comments received following prepublication of the proposed amendments in the Canada Gazette, Part I

On April 20, 2019, HC published proposed regulations to add tramadol to the CDSA and the NCR in the Canada Gazette, Part I. This publication initiated a 60-day comment period during which the Department received feedback from 17 respondents, the majority of whom expressed support for the proposed regulations.

While the comments received were similar to those submitted to HC in 2018, some additional points were noted.

Health care professionals, organizations, and regulatory bodies

While the majority of these stakeholders were generally supportive of the amendments, two did raise concerns.

One stakeholder noted this change would create a burden for people with chronic conditions, especially seniors, as they would have to return to their physicians each time a prescription refill is required.

HC response: Requiring a prescription will provide patients with the opportunity to consult a physician and explore alternate treatment options for their condition. This approach will improve drug selection, dosing, use and monitoring of tramadol products. The increased control is expected to reduce problematic use of tramadol and the risk of its diversion to the illicit market.

The second stakeholder not in support suggested that HC focus its efforts to address the harmful impacts that opioids may present through harm reduction initiatives rather than through regulation.

HC response: HC strives to address issues of public health and safety in a balanced manner. While the amendments will help mitigate the health and safety risks of problematic substance use, HC, through the CDSS, has supported and continues to support measures that reduce the harmful health, social and economic effects of substance use.

Supportive points raised by health care professionals not mentioned in 2018 included the following:

One stakeholder described seeing patients experiencing serious adverse reactions to tramadol, especially the elderly, and stated their belief that placing stricter controls on the drug is a good idea and will help to reduce harm. Another indicated that tramadol should be controlled and regulated the same way as other opioids in Canada and in other countries.

Also in support, one stakeholder noted that the addition of tramadol to the CDSA and the NCR would reinforce practices that are already occurring in some Canadian provinces. For example, hospitals are controlling tramadol in a similar fashion to other narcotics, and tramadol is being included in some prescription monitoring programs.

Finally, one stakeholder expressed concerns that if tramadol is removed from the PDL before the amendments come into force, its oversight and accessibility will be compromised.

HC response: HC will ensure that the transition to remove tramadol from the PDL and the scheduling under the CDSA will be seamless.

Wildlife rehabilitation

Similar to the 2018 consultation, two comments related to the timely access to and availability of alternate drugs for wildlife rehabilitation were received. A comment was also submitted by the provincial veterinarian authority that acknowledged that controlling tramadol would disrupt wildlife practice in its jurisdiction, but that it was nonetheless supportive of the proposed amendments.

HC response: HC has conducted additional targeted consultations with affected stakeholders and determined that their concerns would be most appropriately addressed through the use of the ministerial exemption authority under subsection 56(1) of the CDSA. Veterinarians who provide services to wildlife rehabilitators are encouraged to contact the Department if they believe a subsection 56(1) exemption would be necessary for their practice. HC will continue to work with affected stakeholders over the coming year to mitigate the impact of the amendments on their wildlife rehabilitation practices.

Patients

As in 2018, some stakeholders expressed concerns regarding the barriers to access that the proposed amendments could create. One of these stakeholders also noted the potential stigma they may face when seeking a prescription, thereby creating greater barriers to obtaining a drug that is effective in managing their pain.

HC recognizes that stigma is a barrier to people seeking treatment and other services and, through its CDSS and Canadian Pain Task Force, is working closely with patients experiencing chronic pain and health professionals to help address this issue.

In April 2019, the Government of Canada announced the establishment of the Canadian Pain Task Force to help HC better understand and address the barriers that may prevent people with chronic pain from receiving the health services they need. Through the work of the Task Force, HC aims to promote greater understanding and awareness of the issues related to chronic pain prevention and management.

Through the Pain Task Force and other HC initiatives, the Department is seeking to reduce the stigma associated with prescription opioids and substance use and is encouraging the development of policies and programs designed to support best practices for the prevention and management of chronic pain.

Health Canada's Substance Use and Addictions Program (SUAP) supports a variety of projects that address pain management and substance use. Such projects include educating health professionals on the intersection of substance use and pain management; supporting optimal opioid care pathways and appropriate opioid prescribing for people living with chronic pain; and delivering multidisciplinary pain management programs to reduce opioid misuse.

In addition, HC has allocated funds totalling $3M to the Association of Faculties of Medicine of Canada, the Association of Faculties of Pharmacy of Canada and the Canadian Association for Social Work Education to develop a curriculum for future physicians in the diagnosis, treatment, and management of pain. Additional investments will support optimal opioid care pathways and appropriate opioids prescribing for those living with chronic pain as well as multidisciplinary pain management programs designed to reduce opioid misuse.

Modern treaty obligations and Indigenous engagement and consultation

An assessment of modern treaty implications found that the amendments are not expected to have an impact on Canada's modern treaty obligations.

Indigenous organizations and self-governing bodies were notified when the NTIP and the proposed amendments were published in the Canada Gazette, Part I. None of the feedback received during the comment period identified concerns specific to Indigenous populations.

Instrument choice

The amendments will help protect Canadians from the health and safety risks associated with the unauthorized use of tramadol. Adding tramadol, M1 and M5 to the schedules to the CDSA and NCR is expected to be the most effective approach to facilitate the detection and prevention of unauthorized activities with tramadol, and to help prevent problematic tramadol use.

The amendments will strengthen the surveillance of tramadol prescribing practices, and provide Canadian law enforcement agencies with the authority to take action against unauthorized activities with tramadol and related substances. The amendments will also ensure that activities with M1, M5, and other substances related to tramadol are regulated.

Regulatory analysis

Benefits and costs

A cost-benefit analysis (CBA) was conducted to assess the impacts of the amendments on potentially affected stakeholders (i.e. pharmaceutical industry, patients, health practitioners, pharmacists, wildlife rehabilitation service providers, the Government of Canada, and provincial and territorial governments). All identified costs and benefits are assessed in incremental terms by considering changes that will only occur as a result of the amendments.

Identified impacts are quantified and monetized to the extent possible. Where this is not possible due to data limitations or a lack of sufficient information, the impacts are assessed qualitatively. Together, the quantified and non-quantified impacts provide a more complete picture of the costs and benefits to stakeholders and allow for an adequate assessment of the amendments' net impact.

All quantifiable costs and benefits were estimated over a period of 10 years, from 2020 – 2021 to 2029 – 2030. footnote 6 This period is considered long enough for all the costs and benefits to manifest themselves sufficiently.

All costs and benefits are expressed in 2017 constant Canadian dollars. A 7% real discount rate is used to estimate the present value (PV) of the quantified and monetized impacts, and all values are discounted to the year 2020. The CBA estimates have not been updated since the CGI publication, as the assumptions regarding the efforts and resources that the stakeholders will invest remain unchanged.

The amendments will benefit Canadians, as they will help mitigate the health and safety risks associated with the growing utilization (including problematic use) of tramadol and potentially lessen the associated socio-economic burden. However, the amendments will also increase administrative and compliance burden for the pharmaceutical industry and other stakeholders. These costs and benefits are discussed below. Overall, the amendments are expected to result in net benefits to Canadian society.

Benefits

In Canada, the consumption of tramadol has been increasing over the past few years in contrast to that of other opioids; the volume of tramadol sales per capita rose from 126.9 mg in 2000 to 161.5 mg in 2017. Studies footnote 7 have shown that opioid-related harms due to problematic use are positively correlated with the utilization level of prescription opioids. It is then reasonable to assume that the continued growth in tramadol consumption could result in significant impacts on public health in the long-term.

Adding tramadol to Schedule I to the CDSA and to the schedule to the NCR is expected to result in changes to physicians' prescribing approach and patients' perception and attitudes toward the drug, contributing together to a reduction in the consumption of tramadol products, as it did in other jurisdictions that took a similar approach, like the United Kingdom (U.K.). It is assumed that, in response to these amendments, physicians will follow the same approach (e.g. meeting requirements under the NCR and re-evaluating a patient's health status before deciding to continue with prescribing tramadol) as when prescribing other controlled opioids. At the same time, the increased awareness of patients regarding tramadol's negative health effects, coupled with changes to the Food and Drug Regulations requiring opioid warning stickers and patient information handouts, could help remove the potential misperception of the drug being safer, which will make them more cautious when using the drug.

It is expected that the amendments will contribute to reducing tramadol use, similar to patterns observed in the U.K. and some states in the United States (U.S.) following similar actions taken by these jurisdictions. In the U.S., the states of Kentucky and Arkansas added tramadol to their list of controlled substances in 2008 and 2009, respectively. While consumption of tramadol continued to grow in other states that did not take similar actions, the use of tramadol in Kentucky and Arkansas decreased by 4% and 31%, respectively. At the federal level, there is no readily available information on potential reduction of tramadol use following the scheduling of the substance by the U.S. in 2014.

Similar to the two U.S. states mentioned above, a study footnote 8 in the U.K. indicated that the U.K. witnessed a 13% drop in the monthly utilization of tramadol after the opioid was controlled in 2014. While it cannot be stated with a high degree of certainty that these actions were the only reasons for these total reductions, the statistics presented above suggest that the controls placed on tramadol contributed to a large degree to the reductions observed in these countries. Similar to those jurisdictions, the amendments are expected to result in a decrease in the utilization of tramadol in Canada. This could translate into a reduction in the incidence of tramadol-related adverse events, with associated reductions in morbidity and premature mortality cases.

Reduction in morbidity cases and hospital visits

Between 2006 and March 2020, there were 94 reported cases of abuse-related adverse health events linked to tramadol use. It is expected that the reduction in the use (including problematic use) of tramadol will lead to a reduction in the incidences of adverse health events and the need for medical intervention. This will potentially result in cost savings to the health care system. The cost savings will only be associated with the number of avoided tramadol-related harmful cases that could have otherwise led to interventions from health emergency services and hospital stays. However, there is no information at the national level that can be used to assess how significant the impact of the amendments will be on preventing these adverse health events. As a consequence, this benefit has not been estimated but is acknowledged qualitatively.

Reduction in premature mortality

Between 2006 and March 2020, there were 27 reported deaths potentially related to tramadol use. The available information on the reported cases does not distinguish between intended suicides and accidental deaths. However, the June 2018 “National Report: Apparent opioid-related deaths in Canada” indicated that 92% of the deaths associated with opioids were unintentional. It is therefore reasonable to assume that most of the 27 tramadol-related deaths were accidental. Subjecting tramadol to the same strict controls placed on other opioids under the CDSA will help prevent its problematic use and ultimately contribute to reducing the number of cases of premature mortality associated with the substance. The U.K. study found that the number of tramadol-related deaths per 100 000 inhabitants decreased from 0.42 in 2014 to 0.36 in 2015, a 14% decrease after the scheduling of tramadol in 2014. It is expected that, over time, a similar positive outcome will be observed in Canada.

Other benefits

Controlling tramadol will help strengthen monitoring of activities related to tramadol, which will support evidence-based interventions to address any continued risks to Canadians. The amendments will strengthen HC's oversight of legitimate activities with tramadol, and facilitate detection and prevention of diversion to illicit activities.

Costs
Costs to pharmaceutical industry

There are currently 19 Canadian pharmaceutical companies supplying 35 pharmaceutical drugs containing tramadol in the Canadian market. With these amendments, the administrative and compliance activities prescribed by the NCR will need to be undertaken, resulting in incremental costs to the companies. In total, incremental costs to the pharmaceutical industry are expected to be $1.058 million over 10 years (or $150,656 annually).

Administrative costs

Among the 19 Canadian pharmaceutical companies, 5 are operating sites that are not licensed under the CDSA and thus are not authorized to conduct activities with controlled substances. It is assumed that the 5 companies operate a total of 8 sites where activities with tramadol are conducted. In order to continue their activities (e.g. manufacturing, packaging or distributing tramadol) and comply with the amendments, these sites will need to be licensed (licence holders) and persons in charge at these sites will need to

Conducting these activities will result in administrative costs to the 5 companies.

The 14 companies that operate sites that currently hold valid licences to conduct activities with controlled substances will also carry incremental administrative costs as they continue their activities with tramadol, but to a lesser extent in comparison to the 5 companies whose sites will need to become licence holders. Based on available information and feedback from industry, it is estimated that these 14 companies operate 20 sites where activities are conducted with tramadol. These companies will bear administrative cost associated with amendments made to the licences of their sites to include tramadol and will also carry ongoing administrative costs associated with permit applications made by their licence holders to import or export tramadol. In addition, these companies will bear costs related to additional time spent by licence holders on reporting information on tramadol in monthly and annual reports, as well as on the reporting of suspicious transactions. footnote 9

With respect to import/export permits, it is assumed that about 60 permits each year will be required by affected stakeholders.

Completing the activities mentioned above usually involves someone with a technical or scientific background such as a qualified person in charge (QPIC) or alternate QPIC (AQPIC) and someone at the management level such as a senior person in charge (SPIC). The hourly wages of a QPIC/AQPIC and SPIC used for this analysis are $30.40 and $62.00 (adjusted for overhead and in 2017 dollars), respectively. Table 1 presents the activities and time required for QPICs/AQPICs and SPICs to complete each of the administrative tasks.

Table 1: Time associated with various administrative activities (in hours per task)

Administrative task

QPIC or AQPIC

SPIC

Applying for new licences table 1 note * (one-time)

3

1

Renewing existing licences (every three years)

1

0.5

Applying for a criminal record certificate (every three years)

2

2

Applying for import/export permits (as required)

0.75

0.25

Submitting annual reports — New licence holders

2

0.5

Submitting annual reports — Existing licence holders

1

0.5

Submitting monthly reports — New licence holders

18

3

Submitting monthly reports — Existing licence holders

6

3

Reporting suspicious transactions table 1 note ** (as required)

0.17

0

Reviewing and understanding the regulatory requirements table 1 note * (upfront)

4

2

Table 1 note(s)

Table 1 note *

New licence holders only.

Return to table 1 note * referrer

Table 1 note **

Administrative cost related to suspicious transactions is not estimated due to lack of information regarding incident cases.

Return to table 1 note ** referrer

The total incremental administrative cost to the pharmaceutical industry is estimated to amount to $185,690 (or $26,438 annually).

Compliance costs

Some of the current licence holders deal with large volumes of tramadol products which are not necessarily stored in a secure area. With these amendments, site access to these products will need to be controlled and, as a consequence, the products will need to be stored in an area that meets physical security requirements as per the NCR and the Security Directive. It is expected that the current physical security installations at these sites are not large enough to accommodate the volume of tramadol products and will need to be expanded. Based on readily available information on their activities associated with tramadol, it is expected that changes will need to be made to the security installations at three licensed sites, resulting in associated incremental compliance costs. The average cost to modify the security areas at these sites is assumed to be the same as the cost that will be assumed to build a new secure area, as indicated below.

The eight sites that will need to become licence holders will have to establish on-site secure storage areas and apparatus to store controlled substances in order to meet the requirements of the Security Directive, with an average upfront capital cost for each storage area estimated at about $70,000. There will also be a need to spend about $1,000 each year to maintain the security environment for each of these sites. There will be costs arising from the requirement to obtain and renew licences. These costs will consist of fees paid to acquire criminal record certificates for all QPIC/AQPICs and SPIC (five individuals on average per site, $60 per individual) and a $5,082 licensing fee paid upon renewal.

The total incremental compliance costs to affected companies will be $872,452 (or $124,218 annually).

Impact on revenues and profits

The expected reduction in the level of tramadol use may have a negative impact on tramadol sales revenues and potentially the profits of businesses. Evidence from the U.K. and the U.S. indicate that tramadol sales decreased after the substance was scheduled by these jurisdictions. In the U.S., tramadol sales revenue decreased at a faster pace once tramadol was classified as a Schedule IV substance under the Controlled Substances Act. While a decrease can be expected for Canadian businesses as well, there is uncertainty as to the magnitude of such decrease. In addition, given the mix of products being offered and potential therapeutic product substitution, the reduction in sales for one product might be compensated by an increase in sales of another, making the potential impact on company profits uncertain but qualitatively acknowledged.

Costs to patients

Patients may be impacted by the amendments, depending on their particular circumstances. Some patients already have to see their doctor each time they need to get a renewal of their prescription while others receive a prescription which includes a specific number of refills. Since verbal prescriptions and refills of tramadol products currently marketed in Canada will no longer be allowed, patients who would have otherwise obtained a prescription verbally or with refills will need to see their doctor to be reassessed so a decision can be made with respect to whether the patient should continue with the medication and receive a prescription.

Patients will therefore be faced with the inconvenience of having to go to and wait for a doctor to renew their prescriptions. There might be cases where some patients face delays in accessing their medication as they are waiting for an appointment. However, the likelihood of this happening is considered to be very low given that patients can be proactive and schedule an appointment well in advance of running out of their medication. While these impacts are acknowledged, it is not possible to assess them quantitatively because information on the number of patients and the frequency of visits to get a prescription renewed is not readily available.

Costs to health practitioners

With these amendments, health practitioners who are authorized to prescribe will be required to report losses and thefts of tramadol within 10 days of an incident; however, using tapentadol — a similar opioid which is a controlled substance and for which there has never been a report of loss and theft from a health practitioner — as a proxy, it is anticipated that there will be a low risk of loss and theft incidents related to tramadol in health practitioners' clinics.

Costs to pharmacies

As is the case for practitioners, pharmacies will also be required to report losses and thefts within 10 days of an incident. Currently, losses and thefts of tramadol (if any) are unknown given that there is no obligation to report these incidents to the federal government for non-controlled substances. However, using tapentadol, a similar opioid which is a controlled substance, as a proxy, it is anticipated that approximately 20 cases of loss and theft incidents per year related to tramadol may be reported by pharmacies in Canada. It is assumed that a pharmacist will spend approximately an hour per incident to complete a loss and theft report.

In addition, pharmacies will face incremental administrative costs in terms of keeping records and documenting information on tramadol to meet federal and provincial requirements with respect to the distribution of narcotic drugs. There are currently 10 947 licensed pharmacies in Canada who will be affected by the amendments. It is assumed that a pharmacist will spend approximately an hour per year to complete this activity.

Using an hourly wage of $47.71 (adjusted for overhead and in 2017 dollars) for a pharmacist, the total incremental costs to pharmacies to report losses and thefts and to keep records on activities related to tramadol will be $3.186 million (or $453,636 annually).

Costs to wildlife rehabilitation service providers

The impact of the amendments on wildlife rehabilitation service providers is expected to be mitigated by the issuance of subsection 56(1) exemptions as needed. There is no fee associated with the exemption process. Costs to wildlife rehabilitation service providers are thus estimated to be minimal.

Costs to the federal government

The Government of Canada will incur limited incremental costs related to processing permit applications, which are not recovered through fees. Based on the number of permits expected to be received by HC over the analytical period, it is estimated that the total incremental cost to the Government of Canada in processing applications will be $12,750 in PV over 10 years (or $1,815 annually).

HC will also devote effort to processing applications for new licences and the renewal of licences as well as amendments to licences to include tramadol. The level of effort by the Department to process these applications is fully cost recovered through the receipt of licensing fees. Therefore, there is no incremental cost on the Government of Canada associated with this activity.

To support the implementation of the amendments, limited compliance promotion activities such as publishing web materials to continue to raise awareness about the requirements, touching base with targeted stakeholders and responding to enquiries will be undertaken. These activities will be conducted after the amendments are registered and will result only in negligible incremental costs to the Department. Similarly, enforcement activities are not expected to be significant. Based on applications submitted to HC, a pre-licence inspection will take place (when the site is ready) to ensure that non-licensed sites are in compliance with the Security Directive. The Department will incur an upfront cost of $750 to conduct these inspections. The licensed dealers will then fall within the Department's risk-based approach for inspections, which will be conducted as part of normal operations; no resources will be specifically assigned to conduct tramadol-related inspections. Overall, the incremental effort associated with compliance promotion and enforcement activities will be very limited, since these types of activities fall within normal compliance activities, and there will be no change in the manner in which the NCR is currently enforced.

Costs to provincial and territorial governments

Provincial/territorial health care programs might be impacted, as these programs will need to cover the costs associated with additional doctor visits in order for patients to get their prescriptions renewed. Due to limitations of available information, it is not possible to provide a quantitative assessment of these impacts.

Net impacts

The amendments subject tramadol to the same regulatory controls as other opioid analgesics. These amendments are expected to contribute to the protection of public health and public safety, stemming from potential changes in both prescribing practices by practitioners and users' perception and attitude toward the drug, potentially leading to a reduction in the utilization of tramadol. Reduced utilization of tramadol is expected to contribute to reduced incidences of adverse health outcomes associated with tramadol use, including problematic use. While these potential benefits are considered significant, it is not possible to provide quantitative estimates due to the lack of reliable and appropriate data.

The amendments will also impose costs on affected stakeholders. Industry will face incremental administrative and compliance costs in order to continue their activities with tramadol. Patients, practitioners, pharmacists, and federal, provincial and territorial governments will also carry costs, but most of these costs are considered minimal and are discussed qualitatively. The quantified and monetized costs to stakeholders amount to $4.3 million over 10 years or $606,107 on an annualized basis (see tables 2A through 5). Overall, taking into account both quantified and non-quantified impacts and considering the potential health and safety benefits, it is expected that the amendments will result in a net benefit to Canadian society.

Cost-benefit analysis summary
Quantified impacts
Table 2A: Costs to pharmaceutical industry — Administrative costs (in 2017 dollars)

Description of cost

Year 1 table 2 note *

Year 10 table 2 note *

Total (10 years) table 2 note *

Total (PV) table 2 note **

Annualized value table 2 note **

Applying for licences

$1,227

$0

$1,227

$1,147

$163

Acquisition of criminal record certificate

$2,941

$2,941

$11,765

$8,319

$1,184

Renewing a licence

$0

$492

$1,475

$931

$133

Amending licences

$1,229

$0

$1,229

$1,149

$164

Submitting annual and monthly reports

$15,213

$15,213

$152,135

$106,853

$15,213

Keeping records

$0

$8,000

$72,000

$48,712

$6,935

Applying for import/export permits

$0

$2,301

$20,706

$14,009

$1,994

Reviewing and understanding the amendments

$4,890

$0

$4,890

$4,570

$651

Total costs

$25,501

$28,947

$265,426

$185,690

$26,438

Table 2 note(s)

Table 2 note *

Costs are undiscounted.

Return to table 2 note * referrer

Table 2 note **

Costs are discounted to 2020.

Return to table 2 note ** referrer
Table 2B: Costs to pharmaceutical industry — Compliance costs (in 2017 dollars)

Description of cost

Year 1 table 3 note *

Year 10 table 3 note *

Total (10 years) table 3 note *

Total (PV) table 3 note **

Annualized value table 3 note **

Licensing fees (payment of fees)

$0

$40,656

$121,968

$77,002

$10,963

Criminal record certificate fees

$2,400

$2,400

$9,600

$6,789

$967

Physical security

$772,200

$11,000

$871,200

$788,661

$112,288

Total costs

$774,600

$54,056

$1,002,768

$872,452

$124,218

Table 3 note(s)

Table 3 note *

Costs are undiscounted.

Return to table 3 note * referrer

Table 3 note **

Costs are discounted to 2020.

Return to table 3 note ** referrer
Table 2C: Costs to pharmaceutical industry — Total costs (in 2017 dollars)

Description of cost

Year 1 table 4 note *

Year 10 table 4 note *

Total (10 years) table 4 note *

Total (PV) table 4 note **

Annualized value table 4 note **

Total administrative costs

$25,501

$28,947

$265,426

$185,690

$26,438

Total compliance costs

$774,600

$54,056

$1,002,768

$872,452

$124,218

Total costs

$800,101

$83,003

$1,268,194

$1,058,142

$150,656

Table 4 note(s)

Table 4 note *

Costs are undiscounted.

Return to table 4 note * referrer

Table 4 note **

Costs are discounted to 2020.

Return to table 4 note ** referrer
Table 3: Costs to pharmacists — Administrative costs (in 2017 dollars)

Description of cost

Year 1 table 5 note *

Year 10 table 5 note *

Total (10 years) table 5 note *

Total (PV) table 5 note **

Annualized value table 5 note **

Filling in the transaction reports

$0

$522,309

$4,700,779

$3,180,339

$452,809

Submitting loss and thefts reports

$0

$954

$8,588

$5,810

$827

Total costs

$0

$523,263

$4,709,367

$3,186,149

$453,636

Table 5 note(s)

Table 5 note *

Costs are undiscounted.

Return to table 5 note * referrer

Table 5 note **

Costs are discounted to 2020.

Return to table 5 note ** referrer
Table 4: Costs to federal government (in 2017 dollars)

Description of cost

Year 1 table 6 note *

Year 10 table 6 note *

Total (10 years) table 6 note *

Total (PV) table 6 note **

Annualized value table 6 note **

Processing import/export permits

$0

$1,173

$10,557

$7,142

$1,017

Doing initial inspections

$6,000

$0

$6,000

$5,607

$798

Total costs

$6,000

$1,173

$16,557

$12,750

$1,815

Table 6 note(s)

Table 6 note *

Costs are undiscounted.

Return to table 6 note * referrer

Table 6 note **

Costs are discounted to 2020.

Return to table 6 note ** referrer
Table 5: Total costs to all stakeholders (in 2017 dollars)

Description of cost

Year 1 table 7 note *

Year 10 table 7 note *

Total (10 years) table 7 note *

Total (PV) table 7 note **

Annualized value table 7 note **

Total costs to pharmaceutical industry

$800,101

$83,003

$1,268,194

$1,058,142

$150,656

Total administrative costs to pharmacists

$0

$523,263

$4,709,367

$3,186,149

$453,636

Total costs to federal government

$6,000

$1,173

$16,557

$12,750

$1,815

Total costs

$806,101

$607,439

$5,994,118

$4,257,041

$606,107

Table 7 note(s)

Table 7 note *

Costs are undiscounted.

Return to table 7 note * referrer

Table 7 note **

Costs are discounted to 2020.

Return to table 7 note ** referrer
Non-quantified impacts

Benefits

Costs

One-for-one rule

Given that the amendments will result in incremental administrative burden to pharmaceutical companies and pharmacies conducting activities with tramadol, the one-for-one rule will apply, and the amendments will be considered an “IN” under the rule.

Administrative costs to impacted pharmaceutical companies

All 19 companies, for a total of 28 sites, will see an increase in administrative burden in order to meet the regulatory requirements as a result of tramadol being listed as a narcotic. The administrative costs will be more significant for 5 of the companies given that the 8 sites they operate are not currently licensed. In order to continue their activities with tramadol, these 8 sites will need to be licensed and persons in charge at these sites will be required to

In addition, the persons in charge at these sites will also need to spend time to review and understand the regulations to ensure compliance with the regulatory requirements.

For the remaining 20 sites that are already licensed, persons in charge will need to

As mentioned earlier, completing the activities mentioned above usually involves a QPIC or AQPIC and an SPIC. The level of effort expressed in terms of time spent by QPICs and SPICs to complete each of the above administrative tasks were estimated based on responses to a questionnaire received from licensed dealers in March 2018 and reported in Table 1. The time spent on these activities is valued using average wage rates of $28.40 and $57.90 per hour (adjusted for overhead and in 2012 dollars) for QPICs and SPICs, respectively.

Administrative costs to pharmacies

In order to continue their business with tramadol, all pharmacies will now be required to keep records of transactions involving tramadol and to report any loss or theft of the drug.

Completing the activities mentioned above usually involves a pharmacist. The time spent (see Table 1 above) on these activities is valued using an average wage rate of $44.50 per hour (adjusted for overhead and in 2012 dollars).

Total administrative costs

As per the requirements of the Red Tape Reduction Act and the Red Tape Reduction Regulations (RTR), the administrative burden costs on all affected industry stakeholders is estimated using the prescribed formula in the RTR over a 10-year period (2020 – 2021 to 2029 – 2030) and discounted to 2012 using a 7% real discount rate. The total incremental administrative burden cost to all affected businesses (pharmaceutical companies and pharmacies) is estimated to be $1,825,507. The annualized incremental cost to affected businesses is estimated to be about $259,911. However, it should be noted that the cost per business is different depending on whether the business is a pharmacy or a pharmaceutical manufacturer. The annualized incremental cost to pharmaceutical companies is estimated to be $13,529. For pharmacies, the annualized incremental cost is estimated to be $246,382. These estimates are updated from the CGI publication to reflect the actual year of registration and years where impacts will be incurred.

Small business lens

Although none of the 19 pharmaceutical companies identified as conducting business with tramadol is a small business, nearly all of the pharmacies in Canada (99.5%) are small businesses; therefore, the small business lens applies.

The total impacts on small business will be $3.17 million over 10 years (or $451,400 annually) [see Table 6]. However, given that the cost per pharmacy is very small and estimated at $41.40 (in 2017 dollars) per year, the amendments are not expected to result in significant costs for small businesses.

Small business lens summary
Table 6: Administrative costs to small businesses

Activity

Annualized value

Present value

Filling in sales reports

$450,545

$3,164,437

Filling in loss and theft reports

$823

$5,781

Total costs

$451,368

$3,170,219

Scheduling tramadol will subject this substance to all the requirements set out in the NCR, including requiring pharmacists to keep record of transactions and reporting any loss and thefts within 10 days. These activities are essential to the effective administration of the NCR and the additional information will assist the Department in taking appropriate measures to deter potential diversion of tramadol and in turn help protect the safety of Canadians. In light of the relatively low cost imposed on pharmacies, a flexible option was not considered necessary.

Regulatory cooperation and alignment

Tramadol is not controlled internationally. The World Health Organization (WHO) Expert Committee on Drug Dependence (ECDD) considered the findings from a critical review of tramadol at its meeting in November 2018, to inform a decision on whether to recommend tramadol for international control under the 1961 or 1971 conventions. The ECDD noted that as an opioid analgesic not subject to international control, tramadol is widely used in many countries where access to other opioids for the management of pain is limited.

While the ECDD was strongly of the view that the extent of abuse and evidence of public health risks associated with tramadol warranted consideration of scheduling, it did not recommend tramadol for international control so that access to this medication would not be adversely impacted, especially in countries or crisis situations where there may be limited or no access to other opioid analgesics.

While international access to medicine in developing countries is an important consideration by the WHO when determining whether a drug should be internationally controlled, this access concern does not apply to Canada, as it has a robust regulatory system that allows predictable medical access to controlled substances by prescription. HC's decision to add tramadol to the CDSA and the NCR was made in consideration of global and national data, such as increasing prescription rates, growing numbers of adverse events, the potential risk to the health and safety of Canadians, and the opioid crisis in general.

Although there is no international obligation to control tramadol, it is regulated as a controlled substance in some jurisdictions, including the U.S. (Schedule IV to the Controlled Substances Act) and the U.K. (class C, Schedule II to the Misuse of Drugs Act 1971). The amendments will align Canadian actions with those jurisdictions.

Within Canada, many provinces and territories (PTs) have prescription monitoring programs that cover a subset of the drugs scheduled under the CDSA. Some provinces, such as Ontario and New Brunswick, also monitor tramadol and other drugs as though they were controlled.

Other PTs, such as Nova Scotia, only monitor certain controlled substances. Scheduling tramadol under the CDSA will make it subject to all PTs' existing monitoring programs, which will promote effective monitoring to detect and prevent diversion.

Strategic environmental assessment

In accordance with the Cabinet Directive on the Environmental Assessment of Policy, Plan and Program Proposals, a preliminary scan was conducted and found no evidence of significant environmental impact. Therefore, a detailed strategic environmental assessment is not required.

Gender-based analysis plus

No gender-based analysis plus (GBA+) impacts have been identified for these amendments.

A preliminary sex- and gender-based assessment was conducted as part of the regulatory development for the amendments to determine whether they will affect a particular socio-economic group differently than others when compared to the status quo. Comparing the sex and gender differences in utilization of tramadol and resulting adverse outcomes, the analysis tries to identify the possibility and evidence that women and men will be affected differently, leading to unequal distribution among genders of benefits or costs from the amendments.

To date, no scientific study has found a gender difference in the movement of tramadol into, through, and out of the human body, and the opioid-related health risks (e.g. respiratory depression, dependence, and addiction) are similar between men and women. Thus, physiologically, tramadol does not generate any differences among genders. However, the route of access to and use patterns of tramadol vary between the two genders.

The assessment of GBA+ implications of the implementation of the amendments did not uncover any potential for either gender to be affected differently than the other compared to their status quo. The patterns indicated above will likely persist after implementation and there will likely be no incremental changes in the differences observed among genders due to controlling tramadol under the CDSA.

In summary, there exist differences between genders in the use of tramadol under the status quo. However, there is no evidence suggesting that the existing differences between genders will be altered as a result of the amendments. Therefore, no GBA+ impacts have been identified for these amendments.

Implementation, compliance and enforcement, and service standards

Implementation

The Order and the Regulations will come into force 365 days after their publication in the Canada Gazette, Part II. This delay in coming into force will provide stakeholders with time to implement any changes required to comply with the new regulatory requirements and apply for a subsection 56(1) exemption if needed. During this time, HC will remove tramadol from the PDL, which does not include ingredients listed in CDSA schedules, effective as of the coming-into-force date of the amendments.

HC will notify stakeholders of the amendments upon publication.

Compliance and enforcement

HC is responsible for issuing licences, permits, and exemptions that authorize activities with controlled substances, and for monitoring compliance with the CDSA regulations and the conditions of exemptions. The Canada Border Services Agency supports compliance monitoring for controlled substances at the border.

Non-compliance may result in administrative sanctions by HC, such as suspension or revocation of a licence or permit, or a referral for criminal prosecution. Federal, provincial and local law enforcement agencies are responsible for taking enforcement action in response to contraventions of the CDSA that are subject to criminal prosecution. Prosecution of these contraventions is the responsibility of the justice system.

Penalties for contraventions of the CDSA are defined in the Act and vary by schedule. For offences committed with a Schedule I substance, the maximum penalty ranges from a $1,000 fine and six months' imprisonment for a first offence of simple possession, to life imprisonment for most other offences if they are prosecuted by indictment. For some indictable offences, a mandatory minimum penalty of one to three years' imprisonment may apply if certain conditions are met.

Provincial and territorial authorities are responsible for professional licensing for practitioners and pharmacists, who are authorized under the CDSA and its regulations to conduct certain activities with controlled substances. These authorities are also responsible for monitoring compliance with any provincial or territorial regulations or practice guidelines regarding controlled substances in their jurisdictions. Non-compliance may result in administrative sanctions by the licensing body. Under certain conditions, the Minister of Health also has the authority to issue notices prohibiting licensed dealers and pharmacists from conducting activities with controlled substances.

Contact

Jennifer Saxe
Director General
Controlled Substances Directorate
Controlled Substances and Cannabis Branch
Health Canada
Main Stats Building
150 Tunney's Pasture Driveway
Ottawa, Ontario
K1A 0T6
Email: hc.csd.regulatory.policy-politique.reglementaire.dsc.sc@canada.ca